By: Daniel Trecroci
On the morning of March 22, people in the diabetes community awoke to the news that the U.S. Food and Drug Administration (FDA) had decided to withdraw Rezulin from the market on March 21. The FDA and endocrinologists advised Rezulin users to switch to Avandia or ACTOS. People who believe they may have been harmed by using Rezulin called their attorneys to pursue litigation against Parke-Davis/Warner-Lambert, which manufactures the drug.
Death Toll Kept Rising
Over one year ago, on March 26, 1999, at an FDA hearing in Washington, D.C., it was disclosed that 42 people had documented cases of liver failure, 28 of whom had died after taking Rezulin. An advisory panel of the FDA ruled at the hearing that Rezulin should no longer be prescribed as a first-line therapy and should only be taken in combination with sulfonylureas, metformin or insulin.
“It was almost unanimous that our expert, outside consultants felt that Rezulin’s benefits still outweighed its risks in certain patient populations,” said John Jenkins, MD, director of a drug evaluation office for the FDA. “Although [the advisory committee] did suggest that if safer alternatives were approved in the same class, their thinking might change.”
One year later, the FDA had 63 documented cases of death as a result of liver toxicity from taking Rezulin. In addition, the drug has been linked to 90 cases of liver failure. With the recent approval of Avandia (manufactured by SmithKline Beecham) and ACTOS (marketed by Eli Lilly and Takeda Pharmaceuticals), there were now safer alternatives available in the same drug class. Thus, the final nail was hammered into Rezulin’s coffin.
“We are now confident that patients have safer alternatives in this important class of diabetes drugs,” said Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research. Woodcock adds that Rezulin was withdrawn after a review of recent test data showed the drug was more toxic to the liver than Avandia and ACTOS.
Approximately 500,000 people were taking Rezulin at the time of its removal.
FDA Officer Called for Rezulin’s Removal
Just last month, Diabetes Health reported the FDA had confirmed 58 deaths in people taking Rezulin, and that Robert I. Misbin, MD, a medical officer for the FDA, had emailed his FDA superiors on January 24, calling for Rezulin to be removed from the market.
“I see no reason why any well-informed physician would continue to prescribe [Rezulin],” Misbin wrote. “Neither do I see any reason why [the] FDA should delay in taking steps to remove [Rezulin] from the market.”
Misbin is a veteran diabetes specialist whose job at the FDA is to evaluate the safety and efficacy of proposed and existing drugs. He was closely involved with the FDA’s approval of Rezulin in January 1997.
Public Citizen’s Anti-Rezulin Crusade
Since July 1998, Sidney Wolfe, MD, director of the consumer protection group Public Citizen, has fought long and hard for Rezulin’s removal from the drug market. Seven months earlier, on December 1, 1997, Rezulin was withdrawn from the United Kingdom (U.K.) drug market after six people had died from liver damage after taking the drug. The British government concluded, “The risks of [Rezulin] outweigh the potential benefits.”
Prior to being removed from the U.K. drug market, Rezulin had been on the market for nine months. For seven of those months, however, there was no warning in Rezulin’s labeling about its potential liver toxicity. It was not until October 31, 1997, that Warner-Lambert established the first liver-monitoring guidelines, recommending that people taking Rezulin have their liver enzymes tested five times during the first year. When it was removed from the U.K drug market, however, the liver-monitoring guidelines for American users were increased to 10 times during the first year. In July 1998, Wolfe and Public Citizen, citing additional Rezulin deaths, began lobbying the FDA to remove the drug from the U.S. drug market. The FDA and Warner-Lambert countered by revising the liver-monitoring guidelines to 11 times per year. In June 1999, the guidelines were increased to 13 times per year.
Now that Rezulin has been recalled, Wolfe laments all of the deaths that could have been prevented since Public Citizen first began taking action.
“The British government took it off the market a long time ago,” says Wolfe. “The question is: Why did the FDA wait so long to take it off the [U.S.] market? Did we really need all of this unnecessary carnage? It’s just another example of how low the standards have gotten at FDA.”
Jenkins says it is difficult to determine what constitutes too many deaths in people taking a drug.
“I think a lot of people out there focused heavily on the risk and we are not discounting that,” says Jenkins. “However, there are also a lot of people who feel that their lives were dramatically improved by Rezulin.”
Anne Peters, MD, an endocrinologist at the University of California, Los Angeles, always tested her Rezulin patients for elevated liver enzymes. She feels Rezulin should have been marked with strong warnings about possible liver damage ever since its approval. She also feels physicians should have regularly monitored patients on Rezulin.
“[Warner-Lambert] didn’t push for it and the FDA didn’t require it, so who is to blame?” asks Peters. “Maybe it’s one of those things that should have happened but just fell through the cracks.”
Peters, a long-time Rezulin advocate, feels that public pressure, coupled with the availability of Avandia and ACTOS, led to Rezulin’s ultimate demise.
“If Avandia had not been approved, Rezulin would still be on the market,” says Peters, who will transfer all of her Rezulin patients to either Avandia or ACTOS.
Jenkins stresses that the FDA’s decision to pull Rezulin was not the result of discussions in the media or public pressure.
“We made our decision based on the science and data, which is really how we have to make our decision if we are going to maintain the public trust,” he says.
Was the System for Approving Rezulin Flawed?
Prior to Rezulin receiving FDA approval in January 1997, John L. Gueriguian, a medical officer for the FDA and the chief reviewer of Rezulin, was removed from his position in the fall of 1996. Gueriguian, who has since ended his 20-year relationship with the FDA, said he told Warner-Lambert it should wait an additional three months for results from a larger study because there were signs of toxicity in clinical trial subjects who took Rezulin. Gueriguian claims Warner-Lambert refused and complained to his FDA superiors. Gueriguian was removed and Rezulin was approved.
Gueriguian has since retained the legal services of the law firm Littlepage and Associates of Houston, which specializes in pharmaceutical cases. Zoe Littlepage of Littlepage and Associates told Diabetes Health that after Rezulin was approved and marketed, Gueriguian’s concerns became a reality.
“People started dying,” says Littlepage.
Diabetes Health reported in its May 1999 issue that in the first randomized FDA trials for Rezulin, one out of 500 patients developed liver enzymes over 800. Wolfe, addressing the FDA advisory panel on March 26, 1999, explained that this was 20 times above normal for a regular liver enzyme test.
Wolfe recently told the Associated Press that the FDA is acting recklessly by fast-tracking the approval of medicines out of fear of alienating the industry. Rezulin, however, was not fast-tracked to approval but was instead given a priority review.
“The Congressional law for fast-tracking breakthrough medicines had not been implemented until the fall of 1997,” says Jenkins. “Rezulin was approved in January 1997. We did not lower the standards for the information Warner-Lambert needed to submit. We simply gave ourselves a shorter period of time to complete our review.”
In the 1980s, it usually took almost three years for the FDA to approve a drug. The drug-review process, however, was sped up in the 1990s after Congress complained it was taking too long to approve life-saving medicines. Today, the average approval time is one year. For drugs which the FDA deems “breakthrough medicines,” the approval process can be knocked down to six months.
“It doesn’t say we have to approve the drug in six months, it just says we have to complete our review in six months,” says Jenkins.
FDA officials say their system of approving drugs works, but they stress that all the side effects of drugs cannot be known until after a drug is approved and is taken by tens of thousands of patients.
Littlepage says that because there was evidence of liver toxicity in clinical trials, Rezulin should not have been approved, let alone marketed. Because of this evidence, Littlepage says it will be difficult for Warner-Lambert to prove they were not liable for Rezulin users’ injuries.
“The action of removing a drug, in response to a request from the FDA, essentially proves that the risks of the drug outweigh its benefits,” says Littlepage.
“Clearly the company had to kill or seriously injure a certain number of people before they were willing to lose their profits on the drug. That number was apparently reached [on March 21].”
Litigation Requests Already Surfacing
On March 16, the law firm Greenberg and Bederman of Silver Spring, Maryland, filed a lawsuit on behalf of the estate of Adrian Seay, who died in March 1999 of irreversible liver damage after taking Rezulin. The lawsuit, filed in the Superior Court for the District of Columbia, charges Warner-Lambert with failing to disclose the safety risks of taking Rezulin.
“Mr. Seay’s death could have been prevented if Warner-Lambert told the truth,” says Robert Jenner, lead attorney for the plaintiff. “Warner-Lambert knew from the very beginning that liver disease was a highly significant adverse reaction.”
According to news releases, Jenner points out that had Seay known of the risks and dangers associated with Rezulin, he would not have taken Rezulin nor been subjected to its catastrophic side effects.
Michael Hackard, of Hackard, Holt and Heller of Gold River, California, is an attorney who specializes in pharmaceutical cases. Hackard says he has been inundated with litigation requests against Warner-Lambert since Rezulin’s removal from the market.
“Since Rezulin’s removal, there have been people calling me from all over the country wanting me to evaluate their cases,” says Hackard. “They suspect that Rezulin has caused them or their family members severe liver damage.”
In early March, Hackard filed a lawsuit against Warner-Lambert on behalf of Dianna Barnett, a 56-year-old Sunday school teacher from Ohio. Barnett took Rezulin for at least two years, and has since been diagnosed with irreversible liver damage. A copy of Barnett’s lawsuit was furnished to Diabetes Health. It alleges that Barnett “took Rezulin alone or in combination with another drug and suffered liver failure requiring a liver transplant as a result of taking said pharmaceutical Product.” In addition, the lawsuit alleges that Warner-Lambert “aggressively marketed and sold Rezulin by misleading potential users about the Product and by failing to adequately warn users of serious dangers which [Warner-Lambert] knew or should have known resulted from the use of Rezulin.” The lawsuit goes on to say, “had individuals such as Plaintiff Dianna Barnett known the risk and dangers associated with Rezulin, and had defendants disclosed such information, Plaintiff would not have taken Rezulin nor been subject to its catastrophic side effects.”
Barnett’s lawsuit seeks an as-yet undetermined amount in damages.
Another Rezulin user, Jerry Hauk, 39, of Ottumwa, Iowa, began taking Rezulin in 1997 after he received a brochure from Parke-Davis touting Rezulin’s benefits for the treatment of type 2 diabetes. He brought the brochure to his doctor and was started on the drug. Hauk took Rezulin for 10 months until he woke up one morning in horrible pain.
“I thought I was having a heart attack,” Hauk explains. “I went to the hospital and stayed there for a few days. They thought that it might be the Rezulin that was making me feel this way, so they took me off it.”
Hauk then found out that he had liver failure and was put on a wait list for a new liver. On June 1, 1998, Hauk received his liver transplant, and when he was recuperating at home, his mother called him and told him to turn on the television. There was a report on how Rezulin had caused the deaths of 21 people and how Public Citizen was petitioning for its removal.
“At the time, I had not heard anything about Rezulin’s side effects,” says Hauk, who decided he wanted to take legal action against Warner-Lambert. After conducting an Internet search, he discovered Hackard, Holt and Heller, which is now representing him.
“It will be similar to the Barnett case,” says Hackard. “We will seek damages for the loss of Jerry’s liver, for the transplant, for his continuing life of disability, and for what he can expect his shortened life span to be.”
Since the liver transplant, Hauk has been taking the anti-rejection drugs Prograf and Prednisone. Recently, his insurance carrier discontinued coverage of the medications, and it is costing Hauk over $1,000 per month to keep his new liver.
“These bills are just going to destroy me,” says Hauk.
Holding Warner-Lambert Liable
Hackard says that a case like Hauk’s is a multi-million-dollar case, which is not taking into account any punitive damages that might be levied against Warner-Lambert.
“Punitive damages can be critical in this case because there is evidence that Warner-Lambert misled the FDA and didn’t fully inform them of the results they had in the preclinical tests,” says Hackard, who is also preparing more lawsuits on behalf of former Rezulin users in Galveston, Texas and St. Louis, Missouri. “Given the nature of all of this, Warner-Lambert should pay a heavy price for what they have done to Rezulin users.”
Stuart A. Kritzer is an attorney in Denver who specializes in product liability cases. He feels that people injured by Rezulin will have to prove that there was a failure to warn about the “true and known liver toxicity of the drug.”
“It’s not what Warner-Lambert has to prove; it’s what the person making the claim has to prove,” says Kritzer.
Kritzer says that claimants will have to prove that Warner-Lambert failed to give warnings or information about potential liver damage. He emphasizes that patients injured by Rezulin who started taking the drug after warning labels and liver-monitoring went into effect will have a harder time proving Warner-Lambert’s liability for their injuries.
“That’s certainly the argument Warner-Lambert is going to make,” says Kritzer. “Obviously what they are going to say is, ‘Eventually we told you of these bad side effects, and from that point forward you can blame your physician.’”
Kritzer compares Warner-Lambert’s problem to the Watergate scandal that brought down Richar
Nixon’s presidency. With Watergate, there was the question: What did the president know and when did he know it? Kritzer says the same can be said in this case.
“What did Warner-Lambert know and when did they know it?” asks Kritzer. “The fact that the label is ultimately changed does not mean that Warner-Lambert did not know earlier of that which they disclosed later.”
Can the FDA or Physicians be Held Accountable?
Since the FDA is a governmental agency, it will be immune to any impending litigation related to liver damage from Rezulin use.
“The FDA is understaffed, underbudgeted and does the best job that it can with its resources,” says Littlepage. “But it is a governmental agency and is thus a political entity. Many things happen which are the result of political pressure and not good science. Rezulin is one example of that.”
Physicians who prescribed Rezulin, however, can be held accountable for injury or death, according to Littlepage.
“When the number of deaths became too high, the FDA required the drug manufacturer to put [warning labels] on the package insert for Rezulin,” says Littlepage. “A package insert is the warnings sheet that is sent to the physician about a drug and which also appears in the PDR [Physicians Desk Reference] which doctors use to educate themselves about drugs. Rezulin went on the market without a [warning label]. The actual language of the warning changed over time, but it did alert the physician to the liver toxicity of drug and recommended monthly blood tests to check liver enzymes.”
Littlepage says that Rezulin-prescribing doctors hold some responsibility if:
(a) they did not check liver enzymes at all or not often enough, or
(b) they did not immediately recognize the early signs of liver problems (which include a swollen or painful abdomen, yellow eyes or skin and brown urine) and did not take the patient off Rezulin as soon as the symptoms appeared.
“Their failure to act promptly could cause a patient to go from just elevated liver enzymes to full liver failure,” says Littlepage.
What if Somebody Took Rezulin, but was not Injured?
Littlepage says that legally, anyone can file a lawsuit, but her law firm will not represent anybody who took Rezulin and did not suffer damage.
“Drug cases are very expensive to prosecute because they involve the review of literally thousands of documents and the testimony of specialized hepatologists and hepatic pathologists who are trained in drug-induced liver failure,” she says. “Another lawyer may have a different opinion.”
Attorneys anticipate civil litigation against Warner-Lambert to last about two to three years.
Wolfe says Public Citizen has asked for criminal prosecution of Warner-Lambert.
“We will, to any extent, provide information to help the FDA make a determination as to whether they should go forward and refer the cases to the Justice Department for criminal prosecution,” says Wolfe.
Repeated calls to Warner-Lambert, asking how they plan to address any civil or criminal prosecution cases against them, were not returned to Diabetes Health.
A $100 Million Problem for Warner-Lambert
With sales of $773 million generated in 1999, the removal of Rezulin will have little impact on Warner-Lambert. On March 28, Warner-Lambert said in an annual report filed with U.S. regulators that it anticipates a one-time cost of about $100 million from the withdrawal of Rezulin.
“The one-time costs associated with the withdrawal, consisting primarily of product returns and inventory write-off, are expected to be approximately $100 million,” Warner-Lambert said in a report filed with the Securities and Exchange Commission.
The company said it expects its blockbuster anti-cholesterol drug Lipitor to post global sales of $5 billion in 2000, and sales of its anti-convulsant Neurontin to grow 10 percent from the $913 million seen in 1999.
“Financially, the loss of Rezulin will have very little impact on Warner-Lambert,” said Jeffrey Kraws, a pharmaceutical analyst for Gruntal and Co.
Rezulin’s withdrawal from the type 2 drug market, however, is expected to reap huge rewards for Avandia and ACTOS. Both drugs were launched in mid-1999 and both work similarly to Rezulin. In 1999, Rezulin garnered $773 million in sales, while Avandia and ACTOS had sales of $133 million and $60 million, respectively, in their abbreviated first year. On March 22, the day after the FDA requested Rezulin’s removal, Warner-Lambert stock was only down 1 3/8 points to 93 5/8, while shares for SmithKline Beecham were only up 7/16 to 67 7/16. Eli Lilly shares were up 1 7/8 to 63 9/16.
Jerry Hauk rejoices in Rezulin’s removal from the market, but thinks about his doctor’s decision to start him on the drug in the first place.
“I never dreamed that there would ever be a risk in taking a diabetes pill,” says Hauk. “I mean, I know that there are side effects with most drugs, but something that is going to cost you your life or liver? I could have just lived with having diabetes. I didn’t think it was all that bad.”
January 1997—Rezulin is given marketing clearance by the U.S. Food and Drug Administration (FDA).
March 1997—Rezulin enters the pharmaceutical market.
October 1997—One person has died from liver failure after taking Rezulin. Warner-Lambert issues a warning letter about possible liver damage risks associated with Rezulin use. As of October 31, 1997, Warner-Lambert incorporates liver monitoring requirements in its labeling for the first time. The requirements specify that patients taking Rezulin should have their liver enzymes tested the first one to two months of therapy, and then every three months for the remainder of the first year (five times during the first year), and then periodically thereafter.
December 1997—It is reported that six people have died worldwide from taking Rezulin, prompting the British government to conclude that “the risks of [Rezulin] outweigh the potential benefits.” The drug is then withdrawn in the United Kingdom. Instead of withdrawing Rezulin in the United States, the FDA suggests that Warner-Lambert modify the liver monitoring requirements. A boxed warning is added to Rezulin’s labeling, which specifies that individuals taking Rezulin should have their liver enzymes measured at the start of therapy, every month for the first six months of treatment, and then every other month for the remainder of the first year (10 times during the first year), and then periodically thereafter.
June 1998—The FDA reveals that 21 people have died from taking Rezulin, prompting Public Citizen to petition the FDA for Rezulin’s removal in the United States.
July 1998—Public Citizen submits its letter to the FDA petitioning for Rezulin’s removal. On July 27, 1998, Warner-Lambert modifies its labeling requirements for the third time. It is now recommended that patients taking Rezulin have their liver enzymes checked at the start of therapy, monthly for the first eight months of therapy, and then every two months for the remainder of the first year (11 times in the first year), and then periodically thereafter.
December 23, 1998—On a national broadcast on ABC’s “Nightline,” it is reported that John Gueriguian, a medical officer for the FDA and the chief reviewer of Rezulin, was removed from his position in the fall of 1996 after he opposed Rezulin’s approval.
March 26, 1999—The number of documented deaths as a result of Rezulin use is at 28. An FDA advisory panel rules that Rezulin can no longer be prescribed as a stand-alone therapy for type 2 diabetes, but in combination with sulfonylurea, metformin or insulin.
May 25, 1999—The glitazone Avandia is approved by the FDA for the treatment of type 2 diabetes.
June 1999—The FDA revises Rezulin’s labeling requirements, advising patients to have liver enzymes tested prior to treatment and then monthly for the first year (13 times in the first year).
July 16, 1999—The glitazone ACTOS is approved by the FDA for the treatment of type 2 diabetes.
January 24, 2000—The FDA confirms that 58 people have died as a result of Rezulin use. Robert I. Misbin, MD, a medical officer for the FDA, emails his FDA superiors calling for Rezulin to be removed from the market.
March 15, 2000—The FDA confirms the Rezulin death toll to be at 63. The American Diabetes Association (ADA) distances itself from Rezulin. The ADA, which until know had extolled the benefits of Rezulin outweighing its risks, reaffirms its backing of Avandia and ACTOS.
March 21, 2000—Rezulin removed from the U.S. diabetes drug market.
Rezulin, Just One of Several Drugs Pulled in Recent Years
These drugs have been recently pulled by the U.S. Food and Drug Administration:
Rezulin—Made by Warner-Lambert. Approved in 1997 and pulled from the market on March 21, 2000.
Rotashield—Made by American Home Products. A vaccine for severe childhood diarrhea called rotavirus. Approved in 1998 and recalled in 1999.
Duract—Made by American Home Products. An anti-inflammatory painkiller. Approved in 1997 and recalled in 1998.
Posicor—Made by Roche. A blood pressure medicine. Approved in 1997 and recalled in 1998.
Redux—Made by American Home Products. A diet drug and part of the fen-phen diet drug cocktail. Approved in 1996 and recalled in 1997.
SmithKline Beecham Encouraging Rezulin Users to Switch to Avandia
SmithKline Beecham, maker of the glitazone Avandia, is working with doctors to help the transition of patients taking Rezulin to safer alternatives. SmithKline Beecham will be offering special services for type 2 diabetes patients to get more information about glitazones.
“Avandia is a clear choice for patients who need to transition from Rezulin to another glitazone, which will allow them to continue therapy with a safer and effective treatment alternative,” said David Krause, MD., vice president and director of clinical research development and medical affairs at SmithKline Beecham.
Over 700,000 patients have started taking Avandia in the United States and more than two million prescriptions have been written. It is approved for the treatment of type 2 diabetes in more than 26 countries.
Liver tests are recommended in all patients prior to initiation of therapy with Avandia and periodically thereafter. Avandia was generally well tolerated in clinical trials. Commonly reported adverse events were upper respiratory tract infections and headaches.
For more information, log on to SmithKline Beecham’s Web site at www.sb.com.
FDA Approves Avandia for Use in Combination with Sulfonylureas
On April 3, SmithKline Beecham announced that the FDA has approved Avandia for use as a treatment in combination with sulfonylureas. Previously, Avandia had been approved for treating type 2 diabetes as both monotherapy and in combination with Glucophage.
In patients inadequately controlled on sulfonylureas alone, the safety and efficacy of Avandia was evaluated in combination with sulfonylureas. In three randomized, double-blind, 6-month studies, both fasting plasma glucose (FPG) and HbA1c were significantly improved in patients given Avandia plus sulfonylureas, as compared to those given sulfonylureas alone. The combination therapy produced and maintained impressive reductions in FPG and HbA1c throughout the duration of the trials.
Now Available in Canada
In another story, on March 30, Health Canada approved Avandia for the treatment of type 2 diabetes, making it the first drug available in Canada to directly treat insulin resistance.
“The Canadian Diabetes Association recommends that Canadians with diabetes discuss any new treatment option with their physician to determine if it is appropriate,” said Donna Lillie, director of research and professional education for the Canadian Diabetes Association.
It is estimated that 1.5 million Canadians are currently diagnosed with diabetes, while another 750,000 people are currently undiagnosed. In addition to Canada’s approval, Avandia has received marketing approval in 26 countries.
FDA to Discuss its Rationale for Pulling Rezulin
The FDA announced that it plans to make a public presentation of the data underlying, and the rationale for, its decision to request the withdrawal of Rezulin. This presentation will be made to the next meeting of the Endocrine and Metabolic Drugs Advisory Committee, tentatively scheduled for May 18 and 19. According to the FDA, that date could change based on availability of committee members.