David W. Anstice, who headed Merck’s business division during Vioxx’s development and sale, spent his third day on the stand Monday as the New Jersey Vioxx trial entered its third week.  Mr. Anstice described for jurors how Merck battled with the FDA for two years over the wording of the Vioxx label. 

Merck had to deal with a 2000-patient study that showed Vioxx users suffered five times as many heart attacks as those taking an older pain-relief alternative, naproxen.  The FDA wanted a notification about Vioxx’s cardiac risks placed in the “warning” section of the Vioxx label. 

Fearing that information about the cardiac risks would hurt the painkiller’s sales, Merck tried to keep the information out of the “warnings’ section of the package insert, preferring that it go in the “precautions” and “clinical studies” sections.  Mr. Anstice stated that Merck predicted a $500 million dollar loss in sales if the cardiac information ended up in the “warnings” section.

Anstice also testified that Merck’s sales reps were not allowed to talk to physicians about any risks that were not included on the Vioxx label.
 
The New Jersey lawsuit was brought by Frederick “Mike” Humeston, a postal worker who began taking Vioxx during the label battle.  He suffered a heart attack two months after he began taking Vioxx.  Merck says the painkiller was not to blame.

The plaintiff’s attorneys are expected to wrap up their side this week, after which Merck will present their witnesses.  The trial is expected to end next month.

Are the scientists who recommend approval of drugs for public use too close to the pharmaceutical industry?  Some members of Congress would like to find out.

U.S. Senator Mike Enzi, R-WY, Chairman of the Senate Health, Education, Labor and Pensions Committee and Senator Edward M. Kennedy, D-MA, Ranking Member of the Committee, have asked the Government Accountability Office (GAO) to review the Food and Drug Administration’s practice of providing conflict of interest waivers to members of its scientific advisory committees.  Panel members on these committees are charged with recommending approval of drug and medical devices for public use.

Enzi and Kennedy were joined in the request by Senator Richard J. Durbin, D-IL.  Senator Durbin is the Assistant Democratic Leader.  In their letter, they say “We are concerned about the process that supports FDA’s decisions to waive conflict of interest rules for scientists with financial ties to the manufacturers of the products under consideration, or their competitors.”

Panel members are meant to provide the FDA with unbiased, independent, and professional advice.  They are required to be free of conflicts of interest concerning any products they recommend for approval.  However, the FDA can grant a waiver if they feel that an expert’s participation is necessary, the financial interests are so small so as not to affect the individual’s service, or if the need for the expertise outweighs the potential conflict due to financial interest.

In the letter to David M. Walker, the Comptroller General, the Senators lay out the FDA’s charter in regards to drug approval.  “The Food and Drug Administration (FDA) has the important responsibility of ensuring that the drugs, medical devices, vaccines, and other products used by the American people are safe and effective.  The scientific advisory committee system at the FDA is meant to provide the agency with unbiased, independent and professional advice on general scientific matters and issues related to the particular products or classes of products.  The scientific expertise provided by the advisory panels is critical to FDA’s ability to fulfill its mission of protecting public health.”

“We are concerned about allegations with regard to FDA’s use of waivers of the conflict of interest requirements,” the Senators continued.    They provided two examples of such potential conflicts of interest.  The first concerned the FDA’s advisory panel on the safety of Cox-2 inhibitors (such as Vioxx), where nearly one-third of the members received a waiver.  The second example described allegations currently under review that one member of a panel considering the safety of silicone-gel breast implants received payments (either directly or indirectly) from the device industry.

“These practices appear to have undermined the public’s faith in the objectivity and fairness of FDA’s advisory committees,” the letter stated.  “Further, there are questions about transparency in FDA’s procedures for forming advisory committees and granting waivers.” 

The Senators asked the GAO to examine the issue and address the following questions, among others:

·Has the proportion of waivers grown over the past decade?  How many of these waivers are for voting rather than non-voting panelists?

·What process exists for determining if a waiver should confer voting or non-voting status?

·Is there evidence that waivers influence voting?  For example, is a member with a financial interest more likely to vote for the product under review (or against it) than a member without a financial interest?

·FDA’s decision to grant a waiver is often based on the need for the individual’s expertise.  What barriers exist to identifying qualified individuals without conflicts?

·How does the FDA screen individuals it is considering for appointment to advisory committees for conflicts of interest?  What procedures does the FDA have in place for identifying alternative individuals with minimal or no potential conflicts?

·Are the agency’s current disclosure statements transparent and appropriately detailed?  How does FDA balance the needs for privacy and the requirements of FOIA (The Freedom of Information Act) versus the need for public disclosure of waiver agreements?

According to Craig Orfield, Spokesman for the Health, Education, Labor and Pensions Committee, the GAO generally takes several months to respond to a request of this type.  While no decision has been made to hold hearings on this topic, he left open that possibility.

Each year, an unimaginable horror occurs to a number of patients in the midst of surgical procedures.

These unfortunate people wake up only to realize they are still in surgery and, while they are able to feel indescribable pain, they are completely paralyzed and unable to move, cry out, or otherwise let the surgical team know they have regained consciousness.         

In an attempt to prevent this somewhat rare medical phenomenon, the American Society of Anesthesiologists, at a meeting in Atlanta, has instituted new measures to monitor patients under anesthetics.

Significantly, however, the group did not recommend the routine use of brain function monitors which are designed to detect brain-waves and determine the level of consciousness with mathematical accuracy.

According to recent data, in one or two out of 1,000 cases, patients wake up, hear noises, or feel extreme pain during surgery. These reports of consciousness during surgery were more frequent in patients who were in unstable condition or trauma victims.

While one-tenth to one-fifth of 1% is statistically small, it amounts to a great many people when you consider the millions of surgeries done worldwide each year. Even that small percentage, however, amounts to 1,000 to 2,000 cases per million.    

After a 2004 lawsuit brought attention the problem, closer monitoring during surgery and discussion with patients after the procedure was encouraged.

The American Society of Anesthesiologists also proposed a checklist protocol for anesthesia equipment to ensure the correct dose is administered and for the careful examination of the patient’s reflex motion as well as blood pressure and heart rate.

The group rejected the general use of brain function monitors even though one study reviewed the machines favorably since, "there is insufficient evidence to justify a standard, guidelines, or absolute requirement that these devices be used."

The monitoring equipment, manufactured by Aspect Medical Systems Inc. of Massachusetts, was introduced in 1996 and costs $9,500 but can be obtained for $5,000 or less, a company spokeswoman said.

The society concluded that brain function monitors would be used on a “case-by-case basis” especially in procedures such as trauma surgeries and Caesarean sections, which do not allow for deep anesthesia. 

The U.S. Food and Drug Administration (FDA) has released its review of implantable cardioverter defibrillator (ICD) and pacemaker (PM) malfunctions for the period from 1990-2002. 

The findings were presented at the Heart Rhythm Society “Policy Conference on Pacemaker and ICD Performance” in Washington, DC.

The study found that thousands of patients were affected by PM and ICD malfunctions during the 12-year period, and that malfunctions were directly responsible for 61 confirmed deaths.   While the study found a decrease over time in the annual number of malfunctioning pacemakers that were removed and replaced in patients (4.6 per thousand), there was an increase in the number of malfunctioning ICDs (20.7 per thousand), especially during the last three years of the study, when more than 50% of the reported malfunctions occurred.

Potential reasons for the increase in ICD malfunctions include the increased complexity of the ICD devices, manufacturing challenges posed by this complexity, and increased reporting by physicians.  The authors stated that ICDs are a rapidly changing technology.  Over the past 10 years, ICDs have shrunk in size, provided more therapeutic features, and increased their memory.  The decrease in size has brought modifications to battery, capacitor, and circuitry design that may account for some of the malfunctions.

The study also concluded that careful monitoring of device performance is needed.  That may include requesting more detailed information from manufacturers before the devices are approved for marketing and while they are in use by the clinical community.  Another important step is finding ways to communicate more effectively with physicians and patients when the devices malfunction. 

“The FDA is committed to continuing to improve the quality of information that patients and doctors have to make decisions about the safe and effective use of these critical, life-saving technologies,” said Scott Gottlieb, MD, FDA Deputy Commissioner for Scientific and Medical Affairs.  “Pacemakers and ICDs have saved many lives and the benefits of the devices clearly outweigh the risks.  All sophisticated medical devices like these have certain risks.  Our challenge remains to uncover these risks, measure them, and make information available to patients and doctors to help guide their personalized decisions about where the benefits of technologies like these outweigh known or potential risks from their use.”

In preparing this report, the FDA reviewed 366 PMA annual reports, covering hundreds of pacemaker and ICD models.  In light of the findings, the FDA is considering doing analyses like this for ICDs and pacemakers on a periodic basis, so they can monitor the malfunction trends.

The FDA is also taking other steps to address the troubling information found in their report.  They have begun to better coordinate their pre and post-market regulation of the devices, insuring that products are closely monitored after they are in clinical use.  They are also considering asking manufacturers for more comprehensive data, and they are exploring ways to better communicate with physicians and patients.

The FDA has also established a defibrillator working group which is exploring the best way the FDA can make information about defibrillator recalls available to physicians and patients.   

The FDA stressed that the vast majority of reported malfunctions did not lead to death or serious injury, and were detected in time to ensure that patients would continue to receive therapy when it was needed.

“It is important for patients to understand that there is no action that they need to take as a result of this report.  It does alert FDA that there is a trend that needs to be addressed and points out the need for the agency to improve the way it regulates these products, and we are doing just that,” said Daniel Schultz, MD, Director of FDA’s Center for Devices and Radiological Health (CDRH).

The FDA has the following top-priority actions underway:

·Increasing CDRH’s ability to obtain critical information about medical device failures so they can communicate this information clearly and rapidly to both physicians and patients, allowing them to make informed medical decisions.

·For ICDs in particular, the formation of a working group so information can be quickly reviewed and evaluated by staff, and shared more rapidly with the public.

·Operational changes in CDRH’s post-market program to track the performance of medical devices once they each the market and are in general use.  These changes include targeting resources to inspect firms that manufacture potentially higher risk devices, the design of an electronic system for adverse event reporting, and developing guidance for companies to insure that annual reports provide the types of information required for prompt and efficient review by the FDA.

Genentech, a leading biotechnology company, announced that it was discontinuing its Phase II study of Avastin in ovarian cancer patients because a significant number of participants developed ruptures of the bowel. 

Although ruptures are a known side effect of the drug, Genentech saw a higher rate in this clinical trial than in previous ones.  Forty-four patients were enrolled in the proposed 53-person study, and five, or 11%,  developed gastrointestinal perforations.  The patients currently enrolled in the study were informed of the findings and, in consultation with their physicians, may choose to either continue or stop the Avastin treatment.

“GI perforations are a known possible adverse event with Avastin; however, we chose to discontinue enrollment in this Phase II study due to the observation of a higher rate seen in this study than in other trials of Avastin in ovarian cancer or other tumor types,” said Hal Barron, M.D., Genentech’s senior vice president, development, and chief medical officer. 

Bowel perforations can cause serious infections because bacteria can leak into the abdomen.  Such ruptures can be treated with surgery or through a regimen of antibiotics.

The decision to discontinue enrollment was made by Genentech in consultation with the FDA.  Genentech spokesman, Neil Cohen, said that Avastin is known to contribute to the development of bowel ruptures in patients who have received chemotherapy or who have undiagnosed bowel obstructions.  According to the company, patients enrolled in the Phase II study had more advanced disease, which typically involves the bowel, and had received more chemotherapy than in previous clinical trails of Avastin in ovarian cancer patients.  Mr. Cohen said that Genentech will continue testing Avastin on ovarian cancer patients who have not received chemotherapy.

Avastin was approved by the Food and Drug Administration in 2004 for the treatment of colon cancer.  It cuts off the blood supply to tumors, and Genentech is testing the drug against other forms of cancer.

Four whistleblowers from a pharmacy in Key West, Florida, are splitting $26 million of a $150 million settlement by international pharmaceutical giant GlaxoSmithKline, after the four partners exposed the drug company’s overcharging Medicare and Medicaid for two drugs used to treat cancer.

GlaxoSmithKline, a firm based in Philadelphia and London, which produces the antidepressant Wellbutrin, was accused of overpricing Zofran (1994-2002) and Kytril (1994-2000), two drugs commonly used to treat nausea in chemotherapy patients.

This case comes on the heals of several others  in which pharmaceutical companies are being sued for discounting the prices of certain drugs to retailers, while charging more to the government’s Medicaid and Medicare programs.

The government maintains that drug manufacturers must charge Medicare and Medicaid programs the “average wholesale price.”

Back in the 1990s, the whistleblowers noticed irregularities in the pricing of Zofran and Kytril, used primarily to treat nausea in chemotherapy patients. They filed their lawsuit in 1995. 

Most of Ven-a-Care’s other cases also started in the 1990s and have been progressing slowly through the legal system. The accused drugmakers are tenaciously defending each action.

Under federal law, whistle-blower cases are filed anonymously, to protect the identity of the insiders who are complaining. Their identity only becomes public when the legal proceedings are well along.

Ven-A-Care’s ongoing unsealed cases that are now out in public, include a massive federal case in Boston with 27 defendants, three cases in Florida with 10 defendants, and two in Texas with four defendants.

In essence, the members of Ven-a-care have become the government’s “experts," testifying in court cases and before Congress.

Identifying instances of fraud has risen in recent years, as federal budgets for Medicare, the government health plan for the disabled and elderly, and Medicaid, the government health plan for the poor, have grown.

This is the fourth major case won by Ven-A-Care, a small pharmacy that specializes in chemotherapy infusions and other injectable drugs to critically-ill cancer and AIDS patients.

According to the pharmacy’s attorney, whistleblowers from Ven-A-Care have saved the government over $700 million.

In a statement issued by GlaxoSmithKline, the firm said that the government knew of its pricing practices for a while, but had not objected. Nevertheless, the firm said it has decided to settle the case, “without admitting any wrongdoing.”

The National Highway Traffic Safety Administration (NHTSA) has announced that Mazda Motor Corporation has stopped worldwide production of the 2006 Mazda5 and recalled 5,500 of the sport utility vehicles because, on certain units, a heat buildup in the exhaust system can occur.

This problem could result in a fire. There have been reports of three fires due to heat buildup in the exhaust system.

The company is instructing owners to bring their vehicles to Mazda dealerships immediately. They will be given a rental or loaner vehicle at no cost while Mazda develops a remedy and makes proper repairs.

Mazda has told customers that the company may take as long as 30 days to repair the vehicles.

Owners should contact Mazda at 1-800-222-5500.

For more information, customers can also contact the National Highway Traffic Safety Administration’s Vehicle Safety Hotline at 1-888-327-4236; (TTY: 1-800-424-9153); or visit http://www.safercar.gov. The NHTSA ID Number is 05V412000

Expert witnesses continued to hammer away at Merck & Co as the latest Vioxx product liability trial moved through its second week. 

On Wednesday, Edward Scolnick, a former Chief Scientist for Merck, testified via videotape about an email he sent to a Merck colleague. The email stated his fear that Vioxx was causing strokes, heart attacks, and other health problems. He called for Merck to do a cardiovascular study to insure that the drug was safe.  Such a study never took place.

Yesterday, University of Washington biostatistician Richard Kronmal said that even short-tem use of Vioxx could double the risk of a heart attack.  He said that Vioxx had severe effects on the vascular system, and that patients who took the painkiller in company-sponsored tests suffered serious damage to their blood vessels almost immediately.  Merck denies that charge and, in cross-examination, Mr. Kronmal acknowledged that other scientists and the FDA did not share his view. 

Merck & Co is being sued by Frederick Humeston, who claims that his 2001 heart attack was caused by Vioxx.  His attorneys have told jurors that Merck was aware of the drug’s risks and failed to warn consumers.  Merck contends that Vioxx only increased cardiac risk if it was taken for over 18 months, and that Mr. Humeston’s two-month Vioxx regimen could not have been the cause of his heart attack.

The drug was pulled off the market by Merck a year ago, disappointing its estimated 20 million users.  Vioxx had been a popular replacement for other prescription pain killers that caused stomach pain or bleeding.

Merck faces over 5,000 Vioxx lawsuits and plans to appeal a recent $253 million liability verdict that was awarded against the company in Texas.

Guidant Corp. issued recalls Thursday for some of its best-selling pacemakers.  Citing problems with the Insignia and Nexus families of implantable pacemakers, Guidant informed physicians that the devices may fail because of problems discovered by the U.S Food and Drug Administration (FDA).

Failures may result in an intermittent or permanent loss of pacing or telemetry, or the appearance of a reset warning message.  According to Guidant, these failure modes can result in serious health complications.  Although no known deaths have resulted from the failures, hospitalizations have occurred, and the company urged patients to consult with their doctors.

This recall affects over 50% of the company’s pacemaker products, and was due to a report issued by the FDA that included trend observations on the Insignia and Nexus pacemaker families.  The report was filed when the FDA completed its most recent inspection of Guidant’s Cardiac Rhythm Management facilities in St. Paul, Minnesota.  According to the FDA, a seal within the pacemaker devices can leak, allowing moisture to affect the electronic circuits.  The problem can occur without warning and can lead to loss of consciousness, and possibly heart failure and death.

The following pacemaker models are affected by the Guidant recall.  They were all manufactured between November 25, 1997 and October 26, 2000:

·    PULSAR MAX Models 1170, 1171, 1270
·    PULSAR Models 0470, 0870, 0970, 0972, 1172, 1272
·    DISCOVERY Models 1174, 1175, 1273, 1274, 1275
·    MERIDIAN Models 0476, 0976, 1176, 1276
·    PULSAR MAX II Models 1180, 1181, 1280
·    DISCOVERY II Models 0481, 0981, 1184, 1186, 1187, 1283, 1284, 1285, 1286
·    CONTAK TR Model 1241
·    VIRTUS PLUS II Models 1380, 1480
·    INTELIS II Models 1483, 1484, 1485, 1384, 1385, 1349, 1499

The FDA has classified Guidant’s recall as a Class I recall, meaning that there is a reasonable probability that the malfunctioning device will cause serious adverse health consequences or death.

While the failures can occur without warning, sometimes a malfunction can be detected by a physician before it causes serious problems.  Guidant has provided information to physicians about ways to identify a leak-related malfunction.  However, Guidant is not aware of any test that will show if a normally functioning pacemaker is likely to fail in the future.

As of July 11, 2005, Guidant had received reports that 69 pacemakers may have failed due to the leakage.  Approximately 18,000 of the affected devices remain in service in the United States and an additional 10,000 are in service in other countries.

This recall follows the June 17th, 2005 recall of 50,000 Guidant Implantable Cardiac Defibrillators, due to faulty insulation in the wiring.  Defibrillators, used primarily by people who suffer from arrhythmia or an irregular heartbeat, are designed to electrically stimulate the heart.  Guidant announced a second defibrillator recall on July 19th, affecting over 25,000 patients.

Joint research done by the Food and Drug Administration and Harvard Medical School, indicates that the number of defects in implantable defibrillators is rising quickly.  According to William Maisel of Harvard Medical School, it is the recent increase of faulty devices that is troubling. More than half of the defects throughout their 12-year study occurred within the last three years. 

According to the study, defibrillator replacements due to these defects has not kept pace with the recalls, indicating that more needs to be done to assist patients and doctors in the replacement of the faulty and life-threatening devices.

Congress is also taking a hard look at Guidant and how the FDA is monitoring the recalls.  Senator Charles E. Grassley, Chairman of the Senate Finance Committee, has requested information from the FDA concerning the faulty defibrillators.  In his letter of July 20th, he cites the death of a young college student whose implantable defibrillator failed due to a short circuit.

Joshua Oukrop, a 21-year-old student who suffered from a genetic heart disease, died earlier this year when his Guidant Prizm 2 defibrillator short-circuited while he was biking.  A month later, Guidant began notifying doctors of the electrical flaw.

Senator Grassley requested post-approval reports for the recalled heart devices and an update on the steps the FDA and Guidant are taking to establish guidelines for device surveillance and the dissemination of information to both physicians and patients.

Grassley has long been an advocate of dissemination of post-approval information on drugs and their possible harmful side effects.  He and Senator Christopher Dodd (D-Conn) have introduced legislation that would create a national data bank of clinical information, and have written a bill which would establish an independent drug safety office within the FDA.  This office would regulate drugs once they are on the market.

It is not clear if Senator Grassley will call for hearings on Guidant’s recalls, but his staff left the door open for that possibility.

The well-known consumer advocacy group Public Citizen is asking the FDA to add black-box warnings to the labels of Viagra, Levitra, and Cialis. The drugs, used to treat impotence, have been linked to an increase in incidences of blindness among patients.  

The petition calls for the FDA to add the highest level of drug warning to the labels of Viagra, Cialis, and Levitra as well as Revatio, a drug used to treat hypertension.

A small number of patients taking prescription drugs to treat impotence have developed non-arteritic ischemic optic neuropathy (NAION), a disease that causes a loss of vision that typically cannot be restored.  NAION is one of the most common causes of abrupt vision loss in older individuals.  

People with diabetes and heart disease are specifically at risk for developing NAION.  Incidentally, these two risk factors are also two of the leading causes of impotence.

In July, two less severe warnings were added to the labels of Viagra, Cialis, and Levitra regarding sudden vision loss but the FDA said that it could not yet be determined if the drugs were the reason for the reported cases of NAION.  

At that time, the FDA advised patients to stop taking the pills and to notify their physician immediately if they experienced a sudden or decreased loss of vision in one or both eyes.  

In order to further examine this risk, however, Public Citizen looked at FDA data and compared the rates of individuals who were taking impotence drugs and those taking Lipitor, a cholesterol lowering drug that is used by people with similar risk factors.  

The findings indicated that the number of reports of NAION per million prescriptions was 18 times higher for Viagra patients and 25 times higher for Cialis patients compared to individuals taking Lipitor.  

Pubic Citizen has argued that this indicates a higher risk of blindness for patients taking impotency drugs than previously acknowledged by the FDA.

Between 1998 and 2004 the FDA reported 48 cases of NAION in individuals taking Viagra.  Other visual problems were reported by an additional 50 people.

Yet out of some 89 million prescriptions that were issued during that time period, only a handful of people actually experienced this adverse risk.

Dr. Sidney Wolfe, the director of Public Citizen’s Health Research Group argues that the FDA must take responsibility to immediately inform consumers about the risk relating to impotence drugs.  The only acceptable solution, he says, is for a black-box warning to be issued.