Rezulin: fast track to failure.

The FDA's expedited review process and a pharmaceutical company's desire for profits unleashed a dangerous diabetes drug on consumers.

In the mid-1990s, the FDA came under criticism for its slow review for approving cancer and AIDS drugs. Responding to that criticism, Congress passed legislation that permitted the agency to allow a priority review of certain pharmaceuticals that represent a major advance in medical treatment.

This accelerated review can cut the red tape that delays the release of promising new drugs. But priority review can also lead to disaster, as consumer protection checkpoints are eliminated.

Certainly, a decision to approve any drug involves a weighing of relative risks and benefits. The greater the benefit and the greater the need, the more likely Americans are to accept a rapid review of a brand-new pharmaceutical. When drugs offer some benefits but are not truly lifesaving, and safer alternatives exist that provide a similar therapeutic value, how willing are Americans to use drugs that are not thoroughly tested? What are we willing to accept as the "human cost" of permitting a priority review of drugs?

The story of the diabetes drug Rezulin, revealed principally through investigative reporting by the Los Angeles Times,(1) gives us insight into the FDA's accelerated approval process for newly proposed medications. It gives us insight into the power of one of the world's largest pharmaceutical companies and the influence that it has over the agency. And, finally, the story of Rezulin, which can cause serious liver damage, is a tragic reminder of the devastation that occurs when big business puts profits over the lives and the well-being of consumers.

Diabetics have a defect in the body's ability to use insulin as it should to metabolize glucose. In people afflicted with Type 1, or juvenile-onset, diabetes, the pancreas fails to produce insulin, the hormone that influences how cells move sugar from the bloodstream. In Type 2 diabetes, also known as adult-onset or diabetes mellitus, blood-sugar levels are higher than normal, but the body still produces insulin. Over time, these patients develop a resistance to insulin, and they lose their ability to produce enough insulin to overcome that resistance. It is estimated that there are 16 million Americans with diabetes, about 90 percent of whom suffer from the adult-onset form of the disease.(2)

In January 1997, the FDA approved troglitazone, traded under the brand name Rezulin. It was designed for use in patients with Type 2 diabetes whose blood-glucose levels were not adequately controlled by other therapies alone. Rezulin was manufactured by Warner-Lambert, Parke-Davis Division, a multinational corporation headquartered in Morris Plains, New Jersey. The drug was hailed as the first one to resensitize the body to insulin and was designed to reduce or eliminate the need for people with Type 2 diabetes to take insulin injections.

Warner-Lambert was sponsoring studies of Rezulin during a turbulent time in its history. In 1995, Warner-Lambert pleaded guilty to a felony in connection with concealing quality-control problems in its drug manufacturing from the FDA and agreed to pay a $10 million fine.(3) This was one of the largest fines ever imposed on a drug manufacturer. The prosecution resulted from a joint inquiry by the FDA and the Justice Department.

After this episode, Warner-Lambert was sorely in need of a drug to permit it to rebound in the financial area and in the world of public opinion. Company officials vowed to put the prosecution behind them and to recommit to developing a new, big-selling drug.

"We have placed our pharmaceutical research dollars squarely behind compounds we firmly believe capable of producing a large health care dividend," the company told its shareholders.(4)

Development of a new drug is an expensive and time-consuming undertaking. After a drug is first tested on animals, it can take many years to get it to the point of FDA approval, provided it is deemed safe and effective.

But Warner-Lambert had no intention of waiting years to gain federal approval. As it wrote in its 1996 mission statement, "Every day a new product fails to reach a market means missed opportunity." Warner-Lambert, fresh off a $10 million fine and felony conviction, had to move quickly to regain its footing.

Warner-Lambert submitted to the FDA its new drug application for Rezulin approval on July 31, 1996. Within a month, because Rezulin was the first in a new class of diabetes drugs, agency officials agreed to a six-month "priority" review. Dr. John Gueriguian, a veteran FDA medical officer assigned to evaluate Rezulin, reviewed the application and recommended on October 9, 1996, that the agency reject the drug after documenting its possible danger to the liver.

Parke-Davis complained about Gueriguian, and senior FDA officials removed him from the review on November 4, 1996, according to Gueriguian and an agency memo.

With Gueriguian gone, the FDA approved Rezulin in January 1997, making it the most quickly endorsed diabetes pill in the agency's 60-year history. The six months it took to make the decision was less than half the normal approval time.

The ever-changing warning label

First label change. When the FDA first approved Rezulin in early 1997, Warner-Lambert made no recommendation for monitoring liver function. There was only a precaution that troglitazone should be prescribed with caution in patients with advanced liver disease.(5) Several months after the company launched Rezulin in March 1997, however, some cases of liver damage began to be reported.

According to the Public Citizen Health Research Group, a consumer advocacy organization, by late October 1997, there were 35 post-marketing reports of liver injury. These included two cases of liver failure--one resulting in a death, one in a transplant.

On October 28, 1997, the FDA and Warner-Lambert responded to these statistics by adding a nonboxed warning to the label about "rare" cases of liver failure and by recommending that liver tests on patients using the drug be done five times during the first year of use.(6)

In addition, the company sent out a "Dear Healthcare Professional" letter that discussed this first warning about liver toxicity. The letter advised of "the incidence of idiosyncratic hepatocellular injury in patients with Type 2 diabetes being treated with Rezulin."(7)

Glaxo Wellcome was the distributor for its version of troglitazone (Romozin) in the United Kingdom. At this time--November 1997--Glaxo voluntarily withdrew the drug from the British market following reports of liver toxicity, including a number of deaths. Glaxo was quoted as saying that the withdrawal was warranted because "the reports were coming in so fast and the events were so serious.... We have sufficient patient safety concerns to suspend marketing of the product."(8)

Within the FDA, Dr. Robert Misbin, a diabetes specialist who had originally supported the agency's approval of Rezulin, was now having serious misgivings. He wrote a report to his supervisors on November 12, 1997, underscoring the severity of liver injury documented a year earlier during Warner-Lambert's clinical trials. He recounted a disturbingly high incidence of hepatitis and jaundice.

According to the Los Angeles Times, "Misbin wrote that it was `reasonable' to estimate that 2 percent, or 12,350 of the 650,000 patients then using Rezulin, would experience some degree of liver injury. He estimated that up to 0.4 percent, or 2,000, would suffer liver injury of about 30 times above normal."(9)

Second label change. At the time of the first labeling change, the FDA asked for reports on additional adverse events associated with Rezulin. By December 1, 1997, the FDA had received about 150 reports, including three documenting deaths from liver failure.(10)

On that date, Warner-Lambert added a boxed warning to the label, and the frequency of liver tests was increased to 10 times in the first year of use.

The company also sent another "Dear Healthcare Professional" letter,(11) and the FDA issued a bulletin recommending that physicians monitor Rezulin patients more frequently for signs of liver injury. In addition, the agency reported, warning information about potential liver toxicity would be more prominently featured in the drug's labeling.(12)

By this time--nine months after the drug first appeared on the market--Rezulin had generated more than $242 million in sales.(13)

Then, in May 1998, a seminal event occurred in the increasingly worrisome Rezulin saga. The National Institutes of Health (NIH) was cosponsoring a study with Warner-Lambert to determine whether Rezulin and other diabetic drugs could prevent the development of diabetes. A volunteer in this study, Audrey LaRue Jones, a 55-year-old high school teacher from East St. Louis, Illinois, developed liver failure and died. Jones was one of 585 patients in the study getting Rezulin.(14)

Jones's death was of strong interest to the FDA and other officials in mid-1998 because it showed that even a patient who was being monitored in an NIH clinical trial could not be saved from liver failure. Citing concern for the safety of the remaining patients, NIH officials banished Rezulin from the trial.(15)

The significance of this death cannot be overstated: It strengthened the suspicion that Rezulin could kill or injure acutely, without a slow or steady climb of liver enzymes, which would permit a physician to stop the drug in time to prevent injury. Very simply, while liver enzyme monitoring might reduce the risk of serious liver problems, such monitoring could not eliminate the risk. This is what the FDA called a "rapid riser," a patient in whom irreversible acute liver failure developed within about a month.

What made the death of this volunteer even more disturbing was information that was subsequently disclosed concerning a top researcher on the project, Dr. Richard Eastman. Eastman was not only a government researcher, but he was also a paid consultant for Warner-Lambert and a member of its "Rezulin National Speakers Bureau," which urged doctors to use the drug. Indeed, Eastman accepted $78,455 in total compensation from Warner-Lambert and its affiliates in payment for his consulting services.(16)

Third labeling change. On July 28, 1998, in the face of at least 25 deaths from liver failure and three additional patients requiring a liver transplant, Warner-Lambert increased the recommended frequency for liver testing. To supplement the label change, the company sent out yet another "Dear Healthcare Professional" letter advising of the modified requirements. "These new liver enzyme monitoring modifications are intended to reduce the risk of rare but serious liver injury, including liver failure leading to transplant or death," the advisory letter read.(17)

At about the same time, Public Citizen petitioned the FDA to withdraw Rezulin in the United States.(18) The organization cited reports of more than 100 patients who had been hospitalized with liver toxicity and at least 26 deaths from liver failure. The total number of reports received by the FDA of Rezulin-associated liver toxicity was more than 560 since March 1997, when the drug was first marketed.

Public Citizen accurately predicted that the latest warning Warner-Lambert was sending to physicians and the minor changes in the labeling were "doomed to the same failure as the previous, similar warning efforts with the drug." The organization concluded its petition by posing a question: "How many more Americans will have to die or require liver transplants before Parke-Davis and the FDA take action to protect people in this country by banning the drug?"(19)

FDA review

After a private meeting between the FDA and Warner-Lambert in March 1999, a company representative asserted that the agency had reaffirmed its confidence in Rezulin. FDA officials, however, were stating contrary opinions in internal e-mail correspondence obtained by the Los Angeles Times.

The newspaper quoted a March 2 e-mail message that was sent by Dr. Saul Malozowski, of the agency's diabetes drug division, to colleagues:

   My question is: How many fatal cases will suffice to put to rest
   [Warner-Lambert's] argument? I believe that one case will be too many. ...
   The number of [liver-]associated deaths with Rezulin ... is in excess of
   anything previously seen with any of the approved [diabetes] drugs.... We
   know now what has happened with Rezulin, and there is not a single piece of
   information to believe that either new or old patients will not develop
   severe or fatal complications with it.(20)

On March 26, 1999, the FDA's Endocrinologic and Metabolic Drugs Advisory Committee reviewed the most recent data on the safety of Rezulin. By this date, 1.5 million patients had been treated with the drug in the United States.(21) Of concern to the FDA was the finding that some patients who took all the precautions set out by Warner-Lambert still died of severe liver toxicity that arose just weeks after they had passed a liver test.

The full-day hearing, held at a Bethesda, Maryland, hotel, was attended by FDA officials, Parke-Davis representatives, scientists, and other people concerned with this issue.(22)

One notable presentation was by Dr. David Graham, a medical epidemiologist in the FDA's Office of Postmarketing Drug Risk Assessment, who presented his findings on liver failure and the risks of troglitazone. He concluded that in 43 cases of acute liver failure investigated by the agency, 38 were probably caused by the drug.(23) Graham stated:

   In [Parke-Davis's] briefing document, they mention a number of potential
   confounding factors that they believe may make these cases too complicated
   to [determine] causality. However, we believe in our judgment and in the
   judgment of a three- to four-member panel of FDA reviewers that in every
   probable case, troglitazone appeared to be responsible, and other factors
   played either no role or were of a minor contributory nature.(24)

Other information Graham presented was equally compelling. He reported that only an estimated 45 percent of Rezulin patients were getting the proper liver testing to detect problems in time to treat them. Thus, the presentation of these statistics provided the company with information that physicians were doing an inadequate job monitoring for the known complications of this drug.

Graham created a model to estimate that among people who used Rezulin for six months, as many as one in 1,800 could have liver failure.(25) And he reported that the FDA believed that it had received reports of only about 10 percent of the liver damage cases that may have occurred among users because there was no law requiring doctors to report side effects.(26)

The panel of scientific experts recommended that the government place stricter limits on the use of the drug and urged that patients take it only when other therapies failed. About 80 percent of all patients who used the drug did so in combination with other diabetes drugs, and the committee found that when used that way, the benefits of Rezulin still outweighed the risks. Accordingly, the committee stopped short of recommending the drug be withdrawn from the market. Instead, the panel told the FDA that Rezulin should not be used on its own unless the label was changed to warn patients that it carried grave risks.(27)

Notably, in the days preceding the hearing, the agency appointed two new members to this advisory panel. Both were members of a private diabetes education group funded only by Warner-Lambert.

The company's spin, however, was predictably duplicitous. Warner-Lambert's press release, issued that day, touted the FDA's reaffirmation of Rezulin for "most" Type 2 diabetes patients. Warner-Lambert hailed the opportunity to "work with the FDA to further refine the label." Noting that the committee voted that the benefits of the drug, when used with other medicine, still outweighed the risks, Dr. Robert Zerbe, the company's research executive, said, "Patients and physicians can feel confident about the value of Rezulin."(28)

Two months later, in May 1999, the FDA approved Avandia, a drug that works the same way as Rezulin but appeared to have less risk. An agency advisory panel investigating Avandia and a similar drug, Actos, which was also under review,(29) found that these drugs showed no sign of liver injury during investigational studies. Avandia and Actos offered new promise for Type 2 diabetics without the risk of liver toxicity posed by Rezulin.

Shortly after, Warner-Lambert changed Rezulin's labeling for a fourth time. On June 16, 1999, the company sent yet another letter to hundreds of thousands of health practitioners. For the first time, the company warned that Rezulin was no longer indicated as initial single-agent therapy (that is, it should not be taken as patients' only diabetic drug). The company also modified the liver function monitoring schedule by extending the period of monthly liver function tests from 10 months to one year, and then quarterly rather than periodically, as previously recommended.(30)

Shake-up in the FDA

On January 6, 2000, there was a staff meeting of specialists at the FDA. One of the attendees was FDA diabetes specialist Misbin, who in 1997 had recommended priority approval of Rezulin. Misbin explained that following the January 6 meeting, "there appeared to be broad agreement that continued marketing of [Rezulin] was not justified." He stated that FDA officials "seriously entertained" declaring Rezulin an imminent hazard. Misbin wrote in a January 24 e-mail to his superiors: "I see no reason why any well-informed physician would continue to prescribe [Rezulin]." Unless the agency withdrew the drug, Misbin warned, "additional cases of preventable liver failure" may occur.(31)

By early March 2000, the divisiveness within the agency became unusually public. Amid mounting pressure to remove Rezulin, a growing number of FDA physicians expressed concern that further delay would claim the lives of diabetics. Their opinions conflicted with those of top FDA administrators who continued to endorse the drug.(32) What made this public dispute so notable was that the turmoil came about amid allegations that the company hid early reports of liver damage.

On March 10, 2000, Dr. Janet McGill, a St. Louis endocrinologist who assisted in Warner-Lambert's early clinical testing of Rezulin, claimed publicly that the company "clearly places profits before the lives of patients with diabetes."(33) McGill focused on Warner-Lambert's handling of adverse events in patients who took Rezulin in two clinical trials. "I believe that the company ... deliberately omitted reports of liver toxicity and misrepresented serious adverse events experienced by patients in their clinical studies."(34)

After reviewing McGill's materials, the FDA's Misbin wrote his own letter to selected members of Congress, faulting the agency's handling of Rezulin. "In the absence of the threat of a congressional hearing," he wrote on March 3, "I see little hope of turning this around until many more patients have died."(35)

On March 21, 2000, the FDA requested that Warner-Lambert withdraw Rezulin from the market.(36) The agency sought the withdrawal within two hours of a meeting that included agency physicians, lawyers, and other specialists. The company initially argued with the agency but eventually agreed.(37)

The FDA said it had concluded that two other drugs--Actos and Avandia--were safer treatments for the millions of Americans with Type 2 diabetes. "Continued use of Rezulin now poses an unacceptable risk to patients," said Dr. Janet Woodcock, head of the agency's Center for Drug Evaluation and Research. "We are now confident that patients have safer alternatives."(38)

Warner-Lambert said it still thought Rezulin's benefits outweighed the risks but decided it "is in the best interest of patients to discontinue marketing Rezulin at this time."(39)

At the time of its withdrawal, it was estimated that 500,000 people were on Rezulin. The drug had then been linked to 90 confirmed reports of liver failures, including 63 deaths.(40) It had generated over $1.8 billion in sales.(41)

The FDA Endocrinologic and Metabolic Drugs Advisory Committee met on May 19, 2000, to review its regulatory decisions with respect to Rezulin. The agency continued to justify its withdrawal of the drug by stating that Actos and Avandia were safer and preferable alternatives.

In a head-to-head comparison of the first nine months that Avandia and Rezulin were on the market, the FDA reviewed statistics that demonstrated that 16 cases of Rezulin-associated liver failure were reported, compared with only two cases of Avandia-associated liver failure. Analyzing this and other data to compare similar patient populations, the Food and Drug Administration noted that Rezulin was five times more likely to result in liver failure than Avandia.(42)

Repeated failures

On March 22, the Los Angeles Times reported,

   At least three federal investigations related to Rezulin have been
   initiated: an inspector general's inquiry into [Eastman's] acceptance of
   consulting fees from Warner-Lambert; an FDA inquiry into [McGill's]
   allegations that the company omitted findings of liver toxicity from a 1994
   clinical trial; and an FDA internal-affairs investigation into how certain
   agency e-mails came into the possession of The Times.(43)

Thus, both Warner-Lambert and the FDA will have to spend much more time explaining their handling of the Rezulin approval process.

And Warner-Lambert will have much explaining to do in court, as well. As of the time of this writing, over 40 lawsuits have been filed in federal courts and even more in state courts, as well as three multidistrict litigation petitions and numerous state class actions. Coordination of efforts among plaintiff attorneys will inevitably lead to more efficient and more streamlined litigation.

It is estimated that each year, 100,000 Americans die of adverse drug reactions and 1.5 million are hospitalized. With the pharmaceutical industry reporting over $100 billion in annual sales, the responsibility for oversight lies with the FDA.

Changes needed

As demonstrated by the ill-fated Rezulin approval process, significant changes need to be made. Drug approvals should be made on a priority basis only when there is a compelling need for a lifesaving drug.

The agency should be immediately suspicious of complaints by pharmaceutical companies about any FDA official--especially one who is critical of a new drug. Post-marketing surveillance of approved drugs needs to be stepped up, and reports of adverse reactions must be scrupulously heeded by the FDA and the pharmaceutical companies.

Both the agency and drug companies need to continue to impress on physicians and pharmacists the importance of reporting adverse events. While educational campaigns in the form of "Dear Doctor" letters are important and necessary, critical safety messages must also be set forth repeatedly in the media to increase the probability that consumers of drugs will receive important information. Patients also need to be attuned to the drugs they are using and ask questions about risks, benefits, and alternatives.

Only when a comprehensive effort is made by the FDA, pharmaceutical companies, and the consuming public can we expect improved safety of products from the drug industry.

Notes

(1.) In June 1999, Los Angeles Times reporter David Willman won the National Press Club's consumer journalism award for his series of articles on Rezulin. Willman's work on Rezulin prompted the FDA to reassess the drug's safety.

(2.) Food and Drug Admin., Talk Paper, FDA Approves Rezulin for Diabetes Patients Poorly Controlled on Insulin Therapy (Jan. 30, 1997).

(3.) David Willman, Drug Maker Hired NIH Researcher, L.A. TIMES, Dec. 7,1998, at A-1.

(4.) Id.

(5.) Troglitazone (Rezulin) Professional Product Labeling, in PHYSICIANS' DESK REFERENCE 2118 (52d ed. 1998). Notably, in an August 4, 1997, press release, Warner-Lambert reported that "adverse reactions to Rezulin therapy are comparable to placebo," noting that the most prevalent adverse events included infection, headache, and pain.

(6.) Public Citizen Petition, Letter to Michael Friedman, M.D., Lead Deputy Commissioner, Food and Drug Administration, from Sidney M. Wolfe, M.D., Director, Public Citizen's Health Research Group (July 27, 1998).

(7.) Letter from William R. Sigmund II, M.D., Vice President, Medical and Scientific Affairs, Parke-Davis, to Health Care Professionals (Oct. 28, 1997) (emphasis added).

(8.) Troglitazone Suspended in U.K. After More Adverse Events, SCRIP, Dec. 5, 1997, at 15. The suspension triggered an 18.5 percent plunge in Warner-Lambert's stock on the New York Stock Exchange.

(9.) David Willman, "Fast Track" Drug to Treat Diabetes Tied to 33 Deaths, L.A. TIMES, Dec. 6, 1998, at A-1.

(10.) Food and Drug Admin., Talk Paper, Patient Testing and Labeling Strengthened for Rezulin (Dec. 1, 1997) [hereafter FDA Talk Paper].

(11.) Letter from William R. Sigmund II, M.D., Vice President, Medical and Scientific Affairs, Parke-Davis, to Health Care Professionals (Dec. 1, 1997).

(12.) FDA Talk Paper, supra note 10.

(13.) Glaxo Halts British Sales of Diabetes Drug, L.A. TIMES, Dec. 2, 1997, at D-3.

(14.) National Inst. of Diabetes and Digestive and Kidney Diseases, News Brief, NIDDK Discontinues Troglitazone Arm of "Diabetes Prevention Program" Clinical Trial (June 4, 1998).

(15.) David Willman, Officials Faulted for Not Following Rules in Rezulin Case, L.A. TIMES, Mar. 21, 2000.

(16.) Willman, supra note 3; David Willman, Two New FDA Panelists Have Ties to Rezulin Maker, L.A. TIMES, Mar. 25, 1999, at A-1.

(17.) Letter from William R. Sigmund II, M.D., Vice President, Medical and Scientific Affairs, Parke-Davis, to Health Care Professionals (July 28, 1998).

(18.) The petition was filed pursuant to 21 C.F.R. [sections] 10.30 to initiate action to ban troglitazone as authorized by 21 U.S.C. [sections] 355(e) of the federal Food, Drug, and Cosmetic Act.

(19.) Public Citizen Petition, supra note 6.

(20.) David Willman, Fears Grow over Delay in Removing Rezulin, L.A. TIMES, Mar. 10, 2000.

(21.) Warner-Lambert Co., New Facts About Rezulin, Mar. 26, 1999 (press release).

(22.) The 470-page transcript of the meeting is available on the Internet at http:/www.fda.gov/ohrms/ dockets/ac/99/transcpt/3499t1.rtf.

(23.) FOOD AND DRUG ADMIN., CTR. FOR DRUG EVALUATION AND RESEARCH, ENDOCRINOLOGIC AND METABOLIC DRUGS ADVISORY COMM., MEETING NO. 72, Bethesda, Maryland (Mar. 26, 1999), at 107.

(24.) Id. at 107-08.

(25.) Id. at 120.

(26.) Id. at 155.

(27.) David Willman, FDA Advised to Restrict Rezulin Use for Diabetes, L.A. TIMES, Mar. 27,1999, at A-1. At the conclusion of the meeting, Dr. Janet Woodcock, head of the FDA's Center for Drug Evaluation and Research, indicated in an interview that she did not share Graham's concerns. David Willman, Diabetes Drug Rezulin Pulled Off the Market, L.A. TIMES, Mar. 22, 2000.

(28.) Warner-Lambert Co., Warner-Lambert Pleased by FDA Advisory Committee Recommendation on Rezulin, Mar. 26, 1999 (press release).

(29.) The FDA approved Actos (pioglitazone) for monotherapy for patients with Type 2 diabetes on July 16, 1999.

(30.) Letter from William R. Sigmund II, M.D., Vice President, Medical and Scientific Affairs, Parke-Davis, to Health Care Professionals (June 16, 1999).

(31.) David Willman, Key Physician Urges Rezulin Be Withdrawn, L.A. TIMES, Feb. 19, 2000.

(32.) Willman, supra note 20.

(33.) Id.

(34.) Letter from Janet B. McGill to Sen. Edward M. Kennedy, as reported in Willman, supra note 31.

(35.) Willman, supra note 20.

(36.) Dep't of Health & Human Servs., Rezulin to Be Withdrawn from the Market, Mar. 21, 2000 (press release).

(37.) Chris Adams & Gabriella Stern, Warner-Lambert to Remove Rezulin from Market Following FDA Reviews, WALL ST. J., Mar. 22, 2000, at A3.

(38.) Lisa Richwine, Warner-Lambert Withdraws Diabetes Pill Rezulin, Reuters, Mar. 21, 2000.

(39.) Warner-Lambert Co., Warner-Lambert Voluntarily Withdraws Rezulin, Mar. 21, 2000 (press release).

(40.) Murray M. Lumpkin, Deputy Center Director, Center for Drug Evaluation and Research, Food and Drug Admin., Troglitazone: Presentation to Advisory Committee (May 19, 2000), http://www.fda.gov/ ohrms/dockets/ac/00/slides/3615s1.htm.

(41.) Marc Kaufman, Controversial Diabetes Drug Is Withdrawn, WASH. POST, Mar. 22, 2000, at A1.

(42.) Lumpkin, supra note 40.

(43.) David Willman, Diabetes Drug Rezulin Pulled Off the Market, L.A. TIMES, Mar. 22, 2000.

Robert K. Jenner practices with the firm of Greenberg & Bederman in Silver Spring, Maryland.