The Upjohn Nightmare

The overprescription of sleeping pills is an overlooked and underaddressed women's health issue. Tranquilizers and sleeping pills are prescribed disproportionately to women in the United States. A nationwide survey of doctors' offices by IMS, Inc. of Ambler, Pennsylvania showed that of the approximately 100 million tranquilizer and sleeping pill prescriptions filled each year, two-thirds are for women. Women are therefore twice as likely to be exposed to the dangerous side effects associated with sleeping pill prescriptions, including "paradoxical reactions" such as increased anxiety or aggression, daytime sedation, confusion, memory loss, impaired learning ability, poor coordination, drowsiness, fatigue, dizziness and possible addiction. These drugs pose special problems for older women who have more difficulty clearing drugs from their systems and are likely to use sleeping pills for extended periods of time.

The rise--and fall?--of Halcion

Upjohn greatly increased these risks for women--and for all users of sleeping prescriptions--with the introduction of Halcion in 1982. Halcion belongs to a class of drugs known as benzodiazepine hypnotics, and has become the most widely prescribed sleeping medication in the United States, with over 11 million prescriptions filled in 1988. It has annual sales of $250 million, with $100 million in the United States alone. Halcion is more popular than other drugs in its class, such as Restoril and Dalmane, because its effects wear off quickly and it therefore tends not to leave users with a next-day "hangover."

In many users, however, Halcion has some far less desirable effects. Many have reported Halcion to cause violent, even deadly, behavior. Last year, the Food and Drug Administration (FDA) tallied the number of hostile acts reported in association with 329 prescription drugs, and Halcion came out at the top of the list, followed by Xanax, another Upjohn medication. One Halcion user, Ilo Grundberg of Utah, was cleared of murder charges in 1989 when a Utah state judge ruled that she was "involuntarily intoxicated" on Halcion when she became violent and shot and killed her 82-year-old mother in 1988. Later in 1989, Grundberg filed a civil suit for $21 million against Upjohn, alleging that the company's negligence caused her mother's death. Upjohn settled the case with Grundberg in August 1991 for an undisclosed amount.

Since 1982, the FDA has received over 2,000 reports of negative reactions to Halcion, induding amnesia, anxiety, anorexia, agitation, bizarre and aggressive behavior, confusion, delirium, depression, paranoia, and more extreme reactions such as seizures, hallucinations and suicidal thinking. A 1987 FDA report noted that Halcion had racked up eight to thirty times as many adverse reaction reports (depending on the reaction) as Restoril and Dalmane combined, even though Halcion was less widely used than either of those two drugs at the time.

Despite these charges of negative and sometimes lethal reactions, Upjohn has continued to market Halcion and insist on the product's safety. It has resisted labelling changes and, through the submission of misleading and perhaps even fraudulent data, misrepresented the drug's serious side effects to worldwide regulatory agencies, induding the FDA, and to the public.

Documents involved in the Grundberg trial suggest that Upjohn submitted incomplete or fraudulent data to the FDA during the approval process for Halcion. They show that Upjohn omitted from summary tables some adverse reactions experienced by healthy male prisoners used as subjects in a 1972 clinical study of Halcion known as protocol 321. Upjohn submitted protocol 321 to regulatory agencies around the world, induding the FDA. In August 1991, an Upjohn official admitted to the Sunday London Express that the summary tables were incomplete.

Dr. Ida Hellander, a researcher at Public Citizen's Health Research Group, says that protocol 321 was "very important" to Halcion gaining FDA approval, and "critical" to its approval in the United Kingdom. In fact, on October 3, 1991, Britain's Committee on Safety of Medicines (CSM) responded to the allegations of incomplete disclosure by suspending sales of Halcion in the United Kingdom.

Upjohn vigorously objected to the suspension and has been granted a December 3 appeals hearing before the CSM. Upjohn spokesperson Kaye Bennett says that "there is no scientific evidence that would merit the action that the U.K took." Bennett says a company re-analysis of data from protocol 321 and from 86 other clinical tests of Halcion indicates the drug is safe.

Upjohn maintains that the omission of some test reactions from the summary of protocol 321 was due only to "transcription errors." Bennett says that the errors were discovered by Upjohn during its preparation for the Grundberg trial, and that the company reported the errors to relevant regulatory agencies.

One recent television program charges, however, that Upjohn not only omitted case reports from the summary of protocol 321, but in fact left critical data out of the reports themselves. A segment of the BBC program "Panorama" which aired October 14, 1991 presents evidence that the company misrepresented the actual results of the trial by not reporting mental disorders experienced by the prisoner-subjects as study outcomes. Walter Buchanan, one of the prisoners interviewed by "Panorama," said that, after taking Halcion, he experienced severe paranoia for a week. He is reported in the study, however, to have experienced paranoia for only one day. Russel Ayers, another prisoner, told Panorama that he dropped out of the study after three days because of severe paranoia, but Upjohn reported him to have successfully completed the trial with only minor memory problems.

The same segment contains an interview with Upjohn official Dr. Robert Straw, who cites another test, protocol 6415, as demonstrating the safety of Halcion. However, in 1984 the FDA prohibited the doctor who conducted the study, Samuel Fuerst, from ever conducting further clinical tests because he had falsified data for several trials conducted for Upjohn, including protocol 6415. According to "Panorama," Fuerst falsified or simply fabricated the data reported in the study.

The Health Research Group has called on the FDA to launch a criminal investigation into Upjohn's conduct. Hellander says the FDA has not responded to the request, but the agency has announced that it is conducting its own investigation. The Health Research Group has also petitioned the FDA to require Upjohn to "add a strong, prominent box warning" that alerts patients and doctors to the high number of reports of adverse side effects associated with Halcion and the fact that the drug becomes ineffective after two weeks of use. In 1989, Upjohn aggressively lobbied the FDA against requiring labelling changes; the agency eventually instructed the company only to add a warning that Halcion might induce amnesia.

European regulatory bodies have taken much stronger action than the U.S. FDA. On October 15, 1991, the European Community Committee for Proprietary Medicinal Products (CPMP) recommended that doctors prescribe Halcion for no more than two weeks, that it never be prescribed to anyone with a history of psychiatric problems, that it be prescribed only if the sleeping disorder is severe and that a dose of .25 milligrams never be exceeded (the U.S. label recommends a dose of .25 mgs but the FDA permits doses of up to .5 mgs). The CPMP is delaying issuing a final recommendation on Halcion until its next meeting on December 10. Dr. Hellander suspects that Upjohn will probably be willing to go along with any labelling changes suggested by the CPMP in order to hold on to its European sales.

Bennett says that the company is working with the CPMP and with individual member countries, and has proposed several steps to improve the safety of Halcion. These include selling smaller package sizes, implementing a pan-European post-marketing surveillance study and making certain labelling changes. Bennett says Upjohn is also engaged in discussions about Halcion with the FDA.

Pushing Depo-Provera

Halcion is not the first Upjohn drug which has endangered women and whose clinical tests have generated charges of misconduct. Upjohn's contraceptive Depo-Provera is marketed throughout the world, even though the FDA has refused to approve it for use as a contraceptive in the United States.

Injected into the arm or buttock in a 150 milliliter dose,one shot of Depo-Provera prevents conception for at least three months. Upjohn aggressively markets the hormonal contraceptive outside the United States, particularly to women in the Third World. According to Upjohn, Depo-Provera is currently registered or approved in more than 90 countries.

Critics of Depo-Provera believe Upjohn is exposing Third World women to serious dangers [see "The Case Against Depo-Provera," Multinational Monitor, February/ March 1985]. Animal tests of the drug required for the FDA approval process found breast tumors in dogs and endometrial cancer in monkeys. According to the National Women's Health Network, animal and clinical studies further link use of the drug with infertility, diabetes and hypoglycemia, anemia, increased risk of blood clots and excessive bleeding leading to a need for hysterectomies.

The largest U.S. human study of Depo-Provera took place at the Grady Memorial Family Clinic in Georgia, from 1967 to 1978. During that time, more than 10,000 women received at least one Depo- Provera injection; many of these women were unaware that they were participating in the trials of an unproven drug, according to an FDA audit. The FDA auditors determined that there were serious deficiencies with the Grady study, including: a high (75 percent) turnover rate, with no long-term follow-up of patients with regard to cancer or other concerns; a failure to report adverse reactions; and failures to follow the 3-month interval between shots specified in the protocol. Despite these problems, the study appeared in the June 1983 issue of the Journal of the American Medical Association with the conclusion that Depo-Provera was not likely to be associated with cancer.

Upjohn spokesperson Laura Herwin says that "the company maintains that Depo-Provera is a safe and effective contraceptive." She says that the most serious side effects of the drug--irregular bleeding, weight changes, loss of libido, mood changes--occur with all hormonal contraceptives. Herwin asserts that no studies indicate that the drug causes cancer in humans, and that the company holds that dogs are an inappropriate model for detecting cancer in humans.

Upjohn's failing health

Though it markets the most popular sleeping pill in the United States, Upjohn's financial health is uncertain. While its sales for the first half of 1991 were up 13 percent to $1.7 billion, industry experts speculate the company may not be able to survive the next few years without merging with another company.

By 1994, Upjohn will lose monopolies on four of its biggest sellers, when patents expire for Xanax, Halcion, Micronase and Ansaid. In 1989, these four drugs brought in $900 million in sales, or one-third of the company's total sales for that year. According to Viren Mehta, a partner in Mehta and Isaly, a New York-based pharmaceutical research house, Upjohn simply does not have "new products ready to take their place."

Upjohn's current weaknesses make it a potential takeover target in an era in which pharmaceutical companies are riding a wave of mergers. The company, which desperately wants to maintain its independence, is an attractive target as well, since it maintains a well-respected research operation.

Upjohn is hoping that a new class of pharmaceuticals called lazaroids will constitute the blockbuster it needs to see its way through the 1990s. Animal research on lazaroids shows that they may be able to inhibit cell death and therefore limit brain damage after head injury, spinal damage or stroke. Craig Baskin of the Chicago-based stock brokerage Duff and Phelps says that lazaroids "could be incredibly significant" for Upjohn because they would be "entering a market devoid of products." Baskin estimates that the drugs, which will probably cost each patient at least $1,200, could generate annual sales of over $500 million. Mehta says that the drug is still several years away from the market, however, and Baskin agrees that they are unlikely to gain FDA approval before 1994.

Upjohn's most recent previous candidate for blockbuster status has fallen short of expectations. Rogaine, an anti-baldness product, was at one time expected to pull in as much as $500 million per year, but it has been a disappointment for the company. Rogaine's sales were hurt by its high price and the limited success of the treatment. (A Consumers Report article quoted the researchers who conducted the Upjohn clinical trials as saying that Rogaine works on only 10 to 20 percent of users.) The drug brought in only $139 million in 1990. Upjohn, which spent an estimated $30 million on marketing Rogaine directly to men through television and print advertising, is now expected to market the product to women. Baskin says that the company will probably begin advertising Rogaine as a cure for women's thinning hair in January 1992.

The Halcion controversy has added to the company's financial woes. Upjohn's stock value fell 5 percent the day Britain suspended Halcion sales. In an ironic twist, the misconduct with which Upjohn has potentially endangered Halcion users is now potentially endangering Upjohn.