On Thursday February 28 at 12:30 PM EST, the House Energy and Commerce Committee will hold a hearing on Minnesota Democrat Rep. Betty L. McCollum’s "Bruce Vento Ban Asbestos and Prevent Mesothelioma Act" (HR 3339); a piece of companion legislation to Sen. Murray’s. The act is dedicated to late Congressman Bruce Vento, who succumbed to mesothelioma in 2000.

Introduced in August, the bill’s proponents hope to get the President’s signature during this session of Congress.

More information from the Mesothelioma Center archives:

• 2/28/07 - Leading Asbestos-Cancer Group Urges Congress to Partner with Them and Support Funding Provisions in Asbestos Ban Legislation
• 2/12/08 - Tell Congress to Ban Asbestos
• 10/4/07 - Sen. Murray’s Asbestos Ban Passes Senate
• 9/4/07 - Environmental Working Group Applauds Senate Panel’s Passage of Landmark Asbestos Legislation
• 8/3/07 - Research Group Applauds Progress on Ban Asbestos Legislation
• 8/2/07 - “Bruce Vento Ban Asbestos and Prevent Mesothelioma Act” honors former MN Congressman, ends use of deadly substance, invests in health care for victims
• 8/1/07 - ADAO Applauds Unanimous Passage of Senator Patty Murray’s Ban Asbestos in America Act by U.S. Senate Committee on Environment and Public Works
• 7/18/07 - ADAO Leadership Testified Before U.S. Senate Committee on Environment and Public Works as Part of Expert Panel on Effects of Asbestos

Working case definition for progressive inflammatory neuropathy among swine slaughterhouse workers, 2007–2008

• Epidemiologic criterion
  • Participation in or close exposure to commercial or private swine-slaughtering operations.
• Clinical criteria
  • New onset of bilateral and relatively symmetric flaccid weakness/paralysis of the limbs, with or without involvement of cranial-nerve innervated muscles.
  • New onset of decreased or absent deep-tendon reflexes at least in affected limbs.
• Diagnostic criteria
  • Electrodiagnostic studies consistent with axonal or demyelinating peripheral neuropathic features in affected limbs and not attributable to an underlying chronic disease process.
  • Neuroimaging consistent with radiculitis, myelitis, or encephalitis.
  • Cerebrospinal fluid protein level >45 mg/dL (with or without pleocytosis).
• Exclusion criterion
  • Identification of an alternative etiology for clinical or diagnostic findings.
• Case classification
  • Confirmed case: Meets epidemiologic criterion, meets both clinical criteria, and has electrodiagnostic studies consistent with axonal or demyelinating features.
  • Probable case: Meets epidemiologic criterion, at least one clinical criterion, and at least one diagnostic criterion.
  • Possible case: Meets epidemiologic criterion and at least one clinical criterion

On October 29, 2007, the Minnesota Department of Health (MDH) was notified by a tertiary-care provider of unexplained neurologic illnesses among workers in a swine slaughterhouse (plant A) in southeast Minnesota. As a result, MDH initiated a detailed investigation at plant A to characterize the outbreak. This report describes the ongoing investigation and outbreak-control measures undertaken by state public health officials and CDC.

Plant A, located in southeastern Minnesota, employs approximately 1,200 workers and processes 18,000 pigs per day. After being notified of the illnesses, MDH investigators initiated active case finding, interviewed workers at plant A, and reviewed the plant’s occupational health and employment records. As of January 28, 2008, a total of 12 workers at plant A had been identified with confirmed (eight workers), probable (two), or possible (two) progressive inflammatory neuropathy (PIN) (Box). Illness onset ranged from November 2006 through November 2007. Median age of the 12 patients was 31 years (range: 21–51 years); six patients were female. All 12 patients reported being healthy before the onset of neurologic symptoms.

Symptoms ranged from acute paralysis to gradually progressive symmetric weakness over periods ranging from 8 to 213 days. Severity ranged from minor weakness and numbness to paralysis predominantly in the lower extremities affecting mobility. Eleven patients had evidence of axonal or demyelinating peripheral neuropathy by electrodiagnostic testing. Cerebrospinal fluid was obtained from seven patients. All seven had elevated protein levels (median: 125 mg/dL; range: 75–231 mg/dL [normal: 14–45 mg/dL]) with no or minimal pleocytosis (median: 1 cell/dL; range: 1–73 cells/dL in a nontraumatic tap); five patients had evidence of inflammation on spinal magnetic resonance imaging (four patients in peripheral nerves or roots and one patient in the anterior spinal cord).

All 12 patients reported either working at or having regular contact with an area where swine heads were processed (known as the head table), which was located within a larger processing area in plant A known as the warm room. A case-control study was conducted among plant A workers to identify specific risk factors associated with illness. The 10 patients with confirmed or probable cases were included in the study, along with two stratified control groups: 1) a random selection of 48 healthy warm-room workers and 2) all 65 healthy head-table workers. Statistically significant (p<0.05) differences were calculated by chi-square test. Blood samples and throat swabs were collected from all consenting case-patients and controls. As of January 30, laboratory investigations had not identified any infectious agent from the blood and throat-swab specimens that would explain the occurrence of PIN.

Results of the case-control study indicated that case-patients (seven of 10, 70%) were significantly more likely to have worked at the head table than the warm-room controls (12 of 48, 25%) (odds ratio [OR]: 7.0; 95% confidence interval [CI] = 1.3–42.2; p = 0.009). Case-patients also were more likely to have removed brains or remaining skeletal muscle from the pig head (a process known as backing heads) (four of 10, 40%) than controls (two of 46, 4%) (OR: 15.3; CI = 1.8–163.4; p = 0.006). Among head-table workers, case-patients were significantly more likely to have removed brains or skeletal muscle from the head (four of seven, 57%) than head-table controls (eight of 65, 12%) (OR: 9.50; CI = 1.40–70.2; p = 0.01). Illness was not determined to be associated with previous travel outside or within the United States; exposure to chemicals, fertilizers, or insecticides; use of medications; or receipt of previous vaccinations.

An environmental assessment of the plant was conducted on November 28, 2007. Standard personal protective equipment (PPE) used by workers at plant A included hard hats, laboratory coats (including some that were short-sleeved), boots, hearing protection, eye protection, and specialized gloves that varied with the particular task of the worker. A compressed air device was used in the plant to harvest brain tissue from pig heads at the head table. The device was placed into the skull of the pig through the foramen magnum, and the force of the air disrupted the brain material into a liquefied form that made it easier to remove (a technique known as "blowing brains"). This technique caused generation of small droplets and splatter, possibly including aerosolized brain material, to which workers operating the device and others nearby might have been exposed. In response to the investigation, plant A voluntarily suspended harvesting of brains and instituted additional mandatory PPE on November 28, 2007, including face shields and long sleeves, for workers stationed at the head table and other workers who chose to use additional PPE.

Results of Case-Finding Survey

A survey of the 25 federally inspected swine slaughterhouses with >500 employees in the United States indicated that only three plants (plant A in Minnesota and plants in Nebraska and Indiana) reported recent use of compressed air to extract pig brains. To date, no cases of PIN have been identified in association with workers at the Nebraska plant. However, several workers at the Indiana plant have been preliminarily identified with neurologic illnesses and similar histories of exposure to head-processing activities at that slaughterhouse. Further assessments of these patients, and additional measures to identify other workers with illness, are being conducted in Indiana. As a result of this investigation, all three plants have stopped using compressed air to extract brain material.

Reported by: D Lachance, Mayo Clinic, Rochester; S Goyal, PhD, Univ of Minnesota, St. Paul; R Danila, PhD, A DeVries, MD, R Lynfield, MD, Minnesota Dept of Health. J Howell, DVM, J Wyatt, MPH, Indiana State Dept of Health. T Safranek, MD, Nebraska Dept of Health and Human Svcs. E Belay, MD, J McQuiston, DVM, L Schonberger, MD, J Sejvar, MD, Div of Viral and Rickettsial Diseases; S Brueck, National Institute for Occupational Safety and Health; J Adjemian, PhD, B Buss, DVM, J Gibbins, DVM, S Holzbauer, DVM, EIS officers, CDC.

Editorial Note:

This report summarizes an ongoing investigation of PIN, a syndrome that appears to be associated with swine slaughterhouse workers who process pig heads. Several clinical and laboratory features of this illness and the distinctive epidemiology associated with patients appear unique. Pigs slaughtered at plant A have passed inspection by the U.S. Department of Agriculture Food Safety and Inspection Service, and the investigation has not identified any foodborne risk to the general population.

The investigation in Minnesota indicates that PIN appears associated with having worked at the head table, where a compressed-air device was used to extract pig brains. In the process of blowing compressed air into the pig skull, brain material might have been splattered or even aerosolized, and workers might have been exposed through inhalation or contact with mucous membranes. One hypothesis for development of PIN is that worker exposure to aerosolized pig neural protein might have induced an autoimmune-mediated peripheral neuropathy (1,2). Additional investigation of the characteristics and causes of PIN is under way.

Whether compressed-air devices are being used for pig-brain extraction in other slaughterhouses or processing facilities, in the United States or internationally, is unknown. Clinicians should provide CDC with information regarding swine slaughterhouse workers who might have illnesses similar to PIN, including patients with peripheral neuropathy, myelopathy, or features of both. Clinicians who identify such patients should report the cases to their state health department and contact CDC at 770-488-7100.

References

1. 1. Quattrini A. Inflammatory neuropathies. Neurol Sci 2005;26:S6.
2. 2. Tatsumoto M, Koga M, Gilbert M, et al. Spectrum of neurological diseases associated with antibodies to minor gangliosides GM1b and GalNAc-GD1a. J Neuroimmunol 2006;177:201–8.

MDH continues to investigate a cluster of neurological illnesses in workers at a pork slaughtering facility in Austin. To date Minnesota has identified 12 people that share similar symptoms and workplace exposures. The illnesses are characterized by changes in sensation and weakness in the limbs. MDH is working closely with clinicians to identify other possible cases.

MDH, CDC and other partners are investigating a possible role for a procedure that uses high-pressure air to remove brains from the swine head. The procedure using compressed air to harvest swine brain tissue was in both the Minnesota and the Indiana plants. Other plants are also being investigated by CDC and other state agencies.

The potential role of this procedure is not yet known. The cases of illness in Minnesota have an association with working in the area where portions of the head are harvested, including but not limited to harvesting brain tissue. Out of an abundance of caution, pork processing plants in Minnesota, Indiana and Nebraska that have used this high-pressure compressed air technique have voluntarily stopped using it.

Extensive viral and bacteriological testing to find a cause for the illnesses continues. To date, no viral pathogens have been identified. Similarly, bacterial cultures have yielded no conclusive results. MDH is partnering with investigators at CDC, NIOSH, the Indiana Department of Health, the Nebraska Department of Health, the Mayo Clinic, the University of Minnesota, the Minnesota Veterinary Diagnostic Laboratory, and others to determine the cause of these illnesses.

MDH will continue to provide updates as more is learned.

QPP staff and physicians in the Austin and Rochester area recently realized there had been a pattern of cases of neurological illnesses and they seemed to have a workplace in common. The first cases developed symptoms in December 2006 and the other cases developed symptoms over the following several months, up to July 2007. MDH was contacted about a month ago about this cluster of cases and immediately began reviewing clinical findings, interviewing workers for potential exposures and inspecting the plant. MDH learned last week of an additional affected person who was hospitalized.

QPP is cooperating fully with the investigation, which is still underway. The investigation includes interviewing affected and non-affected workers, reviewing clinical data, obtaining diagnostic samples and extensively reviewing potential exposures. To date, a specific cause has not been identified. Health officials are in Austin today to continue the investigation and brief employees, together with QPP officials.

The symptoms of the illness are recognized over several weeks to months and are characterized by muscle weakness and abnormal sensation. In some cases the muscle weakness has been severe. Two individuals were hospitalized; one had an extended stay, including rehabilitation. The illnesses appear to be an inflammatory neurological disease, and in five of the cases the diagnosis was consistent with chronic inflammatory demyelinating polyneuropathy. All individuals have been released and are in various stages of recovery or rehabilitation. There have been no fatalities.

“All of the information we have to date indicates that the general public is not at increased risk for developing this type of illness,” said Minnesota Commissioner of Health Dr. Sanne Magnan. “Also, there is no evidence that the food supply has been affected.”

The eleven cases worked in an area where either swine heads or organs are processed. Thus far in the investigation, none of the cases had apparent associations outside of the workplace.

“This is a very unusual occurrence,” said Dr. Ruth Lynfield, state epidemiologist for MDH. “We are working very hard together with QPP and many partners in public health, environmental health, medicine, veterinary medicine, agriculture, and the swine industry to determine the cause.”

QPP has implemented additional precautionary measures at the plant in conjunction with advice from MDH. MDH investigators are working with the Centers for Disease Control and Prevention and alerting colleagues in the rest of the country to determine if cases are being seen in workers in other pork processing plants around the United States.

MDH officials will provide updates as new information about these illnesses becomes available.

People with type 2 diabetes who have underlying heart disease or who are at high risk of heart attack should talk with their health care provider about the revised warning as they evaluate treatment options. FDA advises health care providers to closely monitor patients who take Avandia for cardiovascular risks.

"FDA has moved expeditiously to review the cardiovascular risks of this drug so that we could inform patients and doctors at the earliest possible time of our findings," said Janet Woodcock, M.D., FDA’s deputy commissioner for scientific and medical programs, chief medical officer, and acting director of the Center for Drug Evaluation and Research. "FDA remains committed to making sure that doctors and patients have the latest information about the risks and benefits of medicines."

Avandia, manufactured by GlaxoSmithKline (GSK), Philadelphia, Pa., was approved in 1999 as an adjunct to diet and exercise to improve control of blood sugar levels. Avandia is approved to be used as a single therapy or used in combination with metformin and sulfonylureas, other oral anti-diabetes treatments.

During the past year, FDA has carefully weighed several complex sources of data, some which show conflicting results, related to the risk of chest pain, heart attacks and heart-related deaths, and deaths from any cause in patients treated with Avandia.

At this time, FDA has concluded that there isn’t enough evidence to indicate that the risks of heart attacks or death are different between Avandia and some other oral type 2 diabetes treatments. Therefore, FDA has requested that GSK conduct a new long-term study to evaluate the potential cardiovascular risk of Avandia, compared to an active control agent. GSK has agreed to conduct the study and FDA will ensure it is initiated promptly.

The revision of Avandia’s existing boxed warning – FDA’s strongest form of warning – includes the following statement:

A meta-analysis of 42 clinical studies (mean duration 6 months; 14,237 total patients), most of which compared Avandia to placebo, showed Avandia to be associated with an increased risk of myocardial ischemic events such as angina or myocardial infarction. Three other studies (mean duration 41 months; 14,067 patients), comparing Avandia to some other approved oral antidiabetic agents or placebo, have not confirmed or excluded this risk. In their entirety, the available data on the risk of myocardial ischemia are inconclusive.

The previous upgraded warning, added to certain diabetes drugs (in class of drugs related to Avandia) on Aug. 14, 2007, emphasized that these types of drugs may worsen heart failure, a condition in which the heart does not adequately pump blood, in some patients. GSK is also developing a Medication Guide for patients to provide additional information about the benefits and risks and safe use of Avandia.

To date, no oral anti-diabetes drug has been conclusively shown to reduce cardiovascular risk. Consequently, the agency also will be requesting that labeling of all approved oral anti-diabetes drugs contain language describing the lack of data showing this benefit.

Today’s action follows recommendations made at the July 2007 joint meeting of FDA’s Endocrine and Metabolic Drugs and Drug Safety and Risk Management Advisory Committees. At the meeting, members voted 22-1 to recommend that Avandia stay on the market, pending a review of additional data. The committee also advised that information warning of the potential for increased risk of heart attacks should be added to the drug labeling.

For more information:
Rosiglitazone maleate (marketed as Avandia, Avandamet, and Avandaryl) Information www.fda.gov/cder/drug/infopage/rosiglitazone/default.htm

FDA Issues Safety Alert on Avandia
www.fda.gov/bbs/topics/NEWS/2007/NEW01636.html

Issues with the leads was first noted in March and physicians were notified. Data accumulated since has prompted Medtronic to stop producing, selling, and distributing the Spring Fidelis leads. Products currently on shelves should be returned to Medtronic.

The defibrillator leads recall does not, however, necessitate the surgical removal of already implanted devices at this time; an adjustment of the defibrillator’s settings is recommended. While the rate of adverse effects is currently less than 1%, it is unknown if this rate will increase as more time passes and leads have been in place for longer.

Adverse effects may include major complications or even death. Medtronic has identified five cases in which the faulty leads may be responsible or a contributing factor in the death of the patient.

Patients currently implanted with affected devices–approximately 268,000 worldwide–should speak with their physicians. A small number of non-Medtronic defibrillators are also fitted with the Sprint Fidelis leads. Patients with another manufacturer’s device that utilize the faulty leads, or those unsure of their leads’ manufacturer, should contact their doctor.

Medtronic’s decision to voluntarily remove its Sprint Fidelis defibrillation leads from the market is in the best interest of patient safety.

These electronic wires are prone to fracture in a small number of patients which can cause the defibrillator to deliver unnecessary shocks or not operate at all. Based on our initial review of reported adverse events, some deaths and major complications have occurred after the leads have fractured.

Defibrillators are life-saving products for patients with a heart rhythm abnormality. We know it can be frightening for a patient to learn that a product they rely on so much might have a serious defect. However, patients can be assured that the likelihood of fracture is very low and FDA is committed to ensuring that the risk to patients is minimized.

Background:

Today, Medtronic announced it was voluntarily suspending distribution of its Sprint Fidelis defibrillation leads because a small number of fractures have been detected. As a result of Medtronic’s action, no more Sprint Fidelis leads will be sold or manufactured and any remaining product should be pulled from inventory and returned to the company. Patients who are implanted with this lead are encouraged to contact their physicians for further information.

Medtronic first notified physicians in March about the fracture rate at that time and the proper method for implantation. Additional data on adverse events accumulated since then has prompted today’s action.

Implantable cardioverter defibrillators (ICDs) and Cardiac Resynchronization Therapy-Defibrillators (CRT-Ds) are used to treat abnormal heart rhythms that can cause the heart to stop suddenly. ICDs and CRT-Ds shock the heart back into normal rhythm by sending a pulse of energy through an electronic wire or lead that is connected to the heart.

When a defibrillator lead is slightly more prone to fracture, it doesn’t mean that every lead will break. Most leads will function well, as is the case with Sprint Fidelis. In the infrequent circumstance where a lead actually breaks, or "fractures," the lead may send false signals that cause inappropriate defibrillator shocks, or therapies such as pacing or shocks may not be delivered.

Current adverse event information indicates that fractures have occurred in less than 1 percent of the approximately 268,000 of these leads implanted worldwide. We don’t know if this rate of adverse events will remain constant or increase over the life of these leads.

FDA considers Medtronic’s action to be a product recall, as defined by FDA regulations, and we will soon be issuing a recall classification for this action. We recognize that some patients and health care professionals might inappropriately interpret the word "recall" to mean that the devices must be surgically removed and returned to the manufacturer. Although the leads should no longer be implanted in patients, we do not mean to imply that these leads should be surgically removed.

The leads continue to function properly in the vast proportion of patients. Although there is no test to predict which lead will fracture, FDA agrees with Medtronic’s recommendation that defibrillator settings be adjusted at the patient’s next scheduled follow-up visit with their doctor. Doing so may increase the likelihood that a fracture will be detected before a patient is harmed.

Neither FDA, Medtronic, nor representatives of the Heart Rhythm Society, recommend the routine surgical removal of a fractured lead because removal carries risks. Instead, physicians should weigh the benefits and risks of either continuing to use the lead with careful monitoring or capping the lead so it is no longer useable and implanting a different model.

Patients should recognize that a small number of Sprint Fidelis leads are used with defibrillators made by manufacturers other than Medtronic. If patients have reason to believe that they have a Sprint Fidelis lead or if they do not know the model of their lead, they should contact their health care professional.

FDA will continue to monitor information on these devices and will take whatever other actions may be necessary.

The Sprint Fidelis leads are used to deliver therapy in defibrillators only, including Implantable Cardioverter Defibrillators (ICDs) and Cardiac Resynchronization Therapy – Defibrillators (CRT-Ds). Approximately 268,000 Sprint Fidelis leads have been implanted worldwide. This action does not affect Medtronic pacemaker patients.

The U.S. Food and Drug Administration (FDA) intends to issue a public statement regarding Medtronic’s decision at www.fda.gov.

Medtronic, its Independent Physician Quality Panel, and Bruce Lindsay, M.D., Professor of Medicine, Director of Cardiac Electrophysiology, Washington University School of Medicine and President of the Heart Rhythm Society (HRS), do not recommend that patients seek prophylactic replacement of Sprint Fidelis leads, as the risks of removal or insertion of another lead exceed the small risk to patients of a lead fracture. Medtronic has provided patient management recommendations that should reduce risks in the affected population and recommends that patients with questions consult their physicians. Information is also available for patients and physicians at www.medtronic.com/fidelis.

This decision is based on a variety of factors that, when viewed together, indicate that suspending distribution is the appropriate action. Based on Medtronic’s extensive performance data, Sprint Fidelis lead viability is trending lower than Medtronic’s Sprint Quattro® lead at 30 months (97.7% Sprint Fidelis vs. 99.1% Sprint Quattro). This difference is not statistically significant; however, if the current lead fracture rates remain constant, it will become so over time. Medtronic believes that given this performance trend and its ability to identify the primary fracture locations, this action is in patients’ best interest.

Lead fractures may present clinically as audible alerts, inappropriate shocks and/or loss of output. Based on current information regarding the 268,000 implanted leads, Medtronic has identified five patient deaths in which a Sprint Fidelis lead fracture may have been a possible or likely contributing factor.

“There is nothing more important to us than the safety and well-being of patients,” said Bill Hawkins, president and chief executive officer of Medtronic. “We take all matters of product quality very seriously and believe this action is the right thing to do given currently available information.”

Medtronic Outreach to Physicians and Patients

In conjunction with Medtronic’s Independent Physician Quality Panel, Medtronic today communicated, via letter and direct outreach with more than 13,000 physicians worldwide, the Sprint Fidelis lead performance data and updated patient management recommendations for patients who are implanted with Sprint Fidelis leads. These recommendations include device programming and patient management recommendations that will ensure a patient’s device is set to more effectively monitor for potential problems and provide an audible alert in the event of lead fractures.

“Medtronic has acted responsibly to address concerns about the possibility of lead fractures and to minimize harm to patients,” said Kevin Hackett, M.D. of Columbus Cardiology Consultants and member of Medtronic’s Independent Physician Quality Panel. “The Physician Panel has reviewed Medtronic’s data and believes they are taking the correct action.”

Information for Patients

Medtronic recommends that patients, who believe they may have a Fidelis lead, consult with their physicians. It is important to note that Medtronic pacemaker patients are not affected by this action. Medtronic will communicate directly to affected patients and encourage them to contact their physicians for more information. Medtronic has established the following website – www.medtronic.com/fidelis – and a toll-free number (1-800-551-5544 ext. 41835) for patients seeking information.

In addition to being equally effective (and in some cases, superior), side-effects were considered less severe and costs considerably lower. Glucophage (metformin) is available in generic form at about $100 for a year’s supply; a month’s supply of Avandia or Actos can be more than twice that.

Consumer Reports created a users’ guide to the information presented in the study, naming the metformin generic as a CR Best Buy. Users for whom metformin alone is ineffective or not well tolerated should consider either glimepiride (Amaryl and generic) or glipizide (Glucotrol and generic). Consumer Reports argued that only the small number of people for whom all of the preceeding drugs prove unusable should consider Actos or Avandia.

While the safety of Avandia is set to be debated before the FDA on July 30th, the drug’s maker GlaxoSmithKline defended the safety and effectiveness of their product in a July 16 press release, arguing that "Avandia is superior in long-term control of blood sugar over five years compared to metformin." However according to a July 16, 2007 article by CNN, the results come as no suprise to diabetes experts:

The conclusions mirror those of an expert panel that leading U.S. and European diabetes groups convened last year, said Dr. David Nathan, diabetes chief at Massachusetts General Hospital. He has received speaker fees from several diabetes drug makers.

Metformin is "an incredibly inexpensive generic drug, which is why we found it so appealing," Nathan said.

Also See:

"Older drugs are the best choice for most people with type 2 diabetes." Consumer Reports. July 2007. <http://www.consumerreports.org/… .htm> (July 17, 2007.)

"Most people with type 2 diabetes should avoid new, heavily advertised drugs–notably Avandia and Actos–because older medications are cheaper, just as effective, and as safe if not safer, according to a new study and a report based on it from Consumer Reports Best Buy Drugs."

"Analysis: Older, cheaper diabetes drugs get high marks." CNN.com. July 16, 2007. <http://www.cnn.com/2007/HEALTH/conditions/07/16/diabetes.drugs.ap/index.html> (July 17, 2007.)

"The clear winner: metformin, sold as Glucophage and generically for about $100 a year. It works as well as other diabetes pills but does not cause weight gain or too-low blood sugar, the analysis found. It also lowers LDL or bad cholesterol."

Press Release: "GlaxoSmithKline Responds to Reviews of Oral Diabetes Medications." GlaxoSmithKline. July 16, 2007 <http://www.gsk.com/media/press-kits/avandia-16july2007.pdf> (July 17, 2007.)

Bolen, et al. "Systematic Review: Comparative Effectiveness and Safety of Oral Medications for Type 2 Diabetes Mellitus." Annals of Internal Medicine. September 18, 2007, Volume 147 Issue 6.<http://www.annals.org/cgi/content/full/0000605-200709180-00178v1> (July 17, 2007.)

“Conclusions: Compared with newer, more expensive agents (thiazolidinediones, α-glucosidase inhibitors, and meglitinides), older agents (second-generation sulfonylureas and metformin) have similar or superior effects on glycemic control, lipids, and other intermediate end points. Large, long-term comparative studies are needed to determine the comparative effects of oral diabetes agents on hard clinical end points.”

Earlier this spring, The New England Journal of Medicine released a study by Dr. Steven Nissen that analyzed the combined results of 42 clinical trials. Their findings indicated that patients on rosiglitazone experienced an increased risk of heart attack by 43% and other cardiovascular-related deaths by 64%.

In the wake of the study results, the FDA requested that Avandia label get a "black box warning," the most serious warning the FDA can request. Additionally, "Safety alert on Avandia" was issued by the FDA which said, in part:

Patients who are taking Avandia, especially those who are known to have underlying heart disease or who are at high risk of heart attack should talk to their doctor about this new information as they evaluate the available treatment options for their type 2 diabetes.

The House Oversight and Government Reform Committee subsequently held a hearing to debate the FDA’s role in evaluating the safety of Avandia. At the hearing, diabetes expert Dr. John Buse testified to feeling intimidated by drug maker GlaxoSmithKline when he expressed misgivings about the drug’s safety as early as 1999.

According to a June 5 article in The New York Times, Buse wrote a letter in March of 2000 to the FDA in which he "criticized [GlaxoSmithKline’s] marketing, saying it employed ‘blatant selective manipulation of data’ to overstate the drug’s benefits and understate its risks."

The drug’s detractors claim overagressive marketing, both to doctors and direct to consumers, despite GlaxoSmithKline’s awareness of the risks will provide for failure-to-warn lawsuits similar to those resulting from arthritis drug Vioxx. Avandia’s supporters, however, cite several studies that do not show a correlating increase in risk.

Debate will likely increase, both over the safety of Avandia and the effectiveness of the FDA’s procedures surrounding drug approval, specifically, the lacking requirement for subsequent safety and effectiveness evaluations by drug makers after receiving approval to market their drug.

In an interview with USA Today, former deputy director of the Division of Drug Risk Evaluation, Rosemary Johann-Liang, the burden of proof required to call a drug’s safey into question is greater than that required to show its effectiveness:

The FDA approves diabetes drugs such as Avandia if clinical trials show they meet the "surrogate endpoint," or goal, of lowering blood sugar, [Johann-Liang] says, but then doesn’t require makers to do follow-up studies of whether patients actually feel better and live longer.

On the other hand, Johann-Liang says, "if there is a safety issue with the drug, it must be confirmed. I just don’t think that that’s appropriate." As a result, "we’re not doing things in a timely way."

Sources & Further Reading

• Rubin, Rita. "FDA scientist says she was reprimanded for warning." USA Today. June 10, 2007. <http://www.usatoday.com/news/health/2007-06-10-fda-insider_n.htm>. June 29, 2007.
• "FDA Issues Safety Alert on Avandia." FDA.gov. May 21, 2007. <http://www.fda.gov/bbs/topics/NEWS/2007/NEW01636.html>. June 29, 2007.
• Saul, Stephanie. “Doctor Says Drug Maker Tried to Quash His Criticism of Avandia.” The New York Times. June 2, 2007. <http://www.nytimes.com/2007/06/02/business/02drug.html?…ei=5070>. June 29, 2007.
• Nissen, Steven E., M.D., and Kathy Wolski, M.P.H. “Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes.” The New England Journal of Medicine. Volume 356:2457-2471; June 14, 2007; Number 24. <http://content.nejm.org/cgi/content/short/356/24/2457>. June 29, 2007.
• Hearing on FDA’s Role in Evaluating Safety of Avandia. Committee on Oversight and Government Reform. June 6, 2007. <http://oversight.house.gov/story.asp?ID=1325>. June 29, 2007.