A new meta-analysis has brought to light some of the statistical evidence that lead to FDA’s April black-box warning on the dangers of atypical antipsychotics for dementia patients. Published in the Oct. 19 issue of the Journal of the American Medical Association, the study indicates that atypical antipsychotics were associated with a slight increase in death among dementia patients. The analysis of 15 clinical trials found 3.5 percent of dementia patients using these drugs died, compared with 2.3 percent who were on placebos. 

    The risks associated of these drugs deserve further analysis, according to experts. But they caution against abandoning use of these drugs in light of these results. “This has to be looked at in perspective,” said lead author Lon Schneider, a professor of psychiatry, neurology, and gerontology at the University of Southern California’s Keck School of Medicine.

    Although not a treatment for dementia itself, antipsychotic drugs are frequently used to treat aggression and delusions associated with the condition, Schneider explained He said these behaviors occur in the majority of dementia patients and are associated with worsening dementia, rapid cognitive decline and earlier mortality.

    According to an accompanying editorial by Peter Rabins and Constantine Lyketsos of Johns Hopkins Medical Institutions, the conditions treated by antipsychotics are present in 60 to 90 percent of dementia patients. In fact, 25 percent of nursing home residents are treated with antipsychotics, they said. 

    The trials used in the analysis tested the efficacy of atypical antipsychotics, which were developed in the 1990s. But two included comparisons with an older conventional antipsychotic, haloperidol, which was also associated with an increased risk of death.

The authors obtained their data from reports of serious adverse events in clinical trials, often unpublished or reported only as posters at conferences, Schneider explained. But individual patient data were not available, the authors said, and data on causes, medical conditions, and other medications, among other things were insufficient for fully understanding the results. 

    For example, it is difficult to pinpoint the mechanisms that link antipsychotics to death. Schneider speculated that some patients might have received high doses and become sedated. This can lead to health problems for elderly people, including heart failure, pneumonia, urinary tract infections, edema, deep vein thrombosis, and pulmonary embolism, especially if they are lying down for a long time.

    In the 17 trials examined by FDA, before the agency issued its April advisory, most of the deaths recorded were heart related or caused by infections, primarily pneumonia.

    If sedation proves to be the cause of at least some of these deaths, the risks associated with antipsychotics can be decreased by lowering doses. 

    Rabins agreed that sedation could have caused some of the deaths. He indicated that these drugs might also increase the risk of patients falling down, which could lead to death. Another possibility, Rabins noted, is that atypical antipsychotics have been associated with changes in the rate at which the heart conducts electrical impulses. 

    The study’s authors expressed hope that the full trial results would be made available for future study, in order to better understand how these patients died.

    “An individual patient meta-analysis might be able to identify characteristics associated with mortality, potentially due to drugs,” they wrote.

Schneider and his colleagues recommended in the paper that doctors use a two- to four- week clinical response window for antipsychotics. If a dementia patient is not showing signs of improvement by four weeks, the doctor should discontinue the drug to decrease the risks. 

    Rabins responded that four weeks might not be enough time to determine efficacy. The patient might need as much as three months. Further study is necessary to determine the right time period, he said.

    In an interview, Rabins emphasized that these results should not prevent people from prescribing antipsychotics for dementia patients. The modest mortality risk is outweighed in many cases by the benefits if symptoms are causing the patient distress or putting caregivers at risk of harm from aggressive behavior. He said that there is a slight tendency to over-prescribe antipsychotics for insomnia or anxiety, and hopefully these findings may eliminate that practice.

    “These medications clearly have an appropriate use and I think there is adequate data to support that,” said Rabins, a professor of psychiatry and behavioral sciences. “This just puts a little more of a burden on the risks and benefits.”

    Schneider noted that the alternatives to antipsychotics – antidepressants, benzodiazepines and anticonvulsants – all carry risks of their own and do not have documented proof of being effective for dementia patients.

“Antipsychotics have offered the best evidence for efficacy,” he said via email. “There is an absence of evidence for the efficacy of these other drugs.” 

Articles

A new meta-analysis confirms the risk of atypical antipsychotics noted by FDA earlier this year. But the reasons for this increased incidence of death remain unclear.

Atypical Antipsychotics Increase Risk of Death for Dementia Patients

Analysts agree that the much-anticipated cervical cancer vaccines in development at Merck and GlaxoSmithKline face a number of obstacles before they can achieve blockbuster status. But they are split over the time it will take to navigate these roadblocks and reach maximum sales potential.

    Both companies are in the final stages of development of vaccines that target strains of the human papilloma virus (HPV), which causes genital warts and, if unchecked, can lead to cervical cancer. Merck is expected to file for FDA approval of Gardasil before the end of 2005. GSK plans to file for approval of its product, Cervarix, in 2005 in the UK and in 2006 in the United States.

    If approved, HPV vaccines could change the cervical cancer screening process in the developed world and open new avenues of prevention in developing countries.

    “This is significant in terms of the unmet need that it will be addressing,” Murray Aitken, senior vice president of corporate strategy at IMS Health, said about Gardasil. “Based on the clinical information to date, this looks like a truly remarkable breakthrough.”

    But even after approval, experts are predicting that the vaccines will face a number of potential hurdles before reaching maximum sales revenues including:

Getting their vaccines included on state government programs in the United States.

Overcoming opposition from political groups in the United States who believe that use of the vaccine could increase teen sexual activity and will want to exclude if from state-mandated programs

Educating the public about the link between HPV and cervical cancer.

Persuading European government programs and domestic private insurers to pay for the vaccines, which are expected to cost $225 to $350 for a course of three injections

    Merck and GSK’s ability to successfully clear these hurdles will determine how quickly they can reach blockbuster status, analysts say.

GSK believes its vaccine will generate impressive revenues quickly. In June, it predicted the global market for HPV vaccines could reach at least $4 billion by 2010. In a Sept. 12 letter to shareholders, Richard Clark, Merck chief executive officer and president, listed a successful launch of Gardasil as one of three “key” factors for improving the company’s performance.

    In an Oct. 11 report, Morningstar analyst Tom D’Amore predicted Gardasil sales of $1 billion in 2009. The previous week, coinciding with Merck’s Phase III results announcement, Bear Stearns analysts John Boris estimated that Gardasil’s sales would reach $1.6 billion by 2010. Although he did not predict exact figures for Cervarix, Boris indicated that sales could be comparable to predictions for Gardasil, saying that the two vaccines could split the market.

    But Stephan Gauldie, analyst at Wood Mackenzie, predicted that it would take 10 to 15 years for HPV vaccine sales to reach their potential. He estimated 2009 sales of $410 million for Gardasil and $258 million for Cervarix.

    “How long is it going to take to get the message across?” Gauldie said in an interview. “We don’t believe that’s going to be rapid.”

Experts agree that after approval, the main challenge for Merck and GSK is getting their vaccines included in government programs.

    Both Gauldie and Boris said that HPV vaccines are likely to be approved in the United States at the federal level by the Advisory Committee for Immunization Practices. But the vaccines are administered through state programs, which may or may not follow federal recommendations. Boris predicted state-level implementation would happen quickly because Merck has already established working groups in a majority of states.

    But Gauldie said state governments might bow to already mounting political pressure from groups who oppose vaccinating 10- to15-year-old children against HPV, a sexually transmitted disease. This could hinder states from including Gardasil or Cervarix in mandatory vaccination programs, he said. Some analysts see a link between HPV vaccines and the political saga of Barr Laboratories’ so-far-unsuccessful attempt to move its morning-after contraceptive, Plan B, to over-the-counter status.

    Evan Myers, a professor of obstetrics and gynecology at Duke University and Merck consultant, said the companies could avoid this problem by emphasizing that preventing cervical cancer is the primary goal of vaccination. The link between HPV and cancer is better known than in previous years, he said.

    “I don’t think there’s as much stigma attached as there would have been 15 years ago,” he said.

    Gauldie and Boris also agreed that inclusion in government-sponsored vaccination programs would take longer in Europe than the United States. Gauldie indicated that Merck and GSK might have to lower prices in order to get the vaccines included in these programs.

    Gauldie predicted that if government programs do not include these vaccines, insurance companies might also be opposed to the high prices. This would also be an issue for older women interested in getting vaccinated.

    “It might be a difficult sell for the insurance companies,” he said.

    Myers disagreed. He believes that various medical professional organizations will recommend vaccinating against HPV, making it impossible for insurance companies to refuse.

If HPV vaccines are adopted, it will be cost-effective for women in developed countries to screen for cervical cancer less frequently, Myers said. In addition, positive tests will be more likely to actually indicate a problem, he said. Current screening programs frequently identify abnormalities of HPV, but relatively few lead to cancer.

    Myers asserted that HPV vaccines could be key in preventing cervical cancer in developing nations, where screening programs are rare or non-existent.

Merck and GSK’s cervical cancer vaccines promise great benefits to women-but there are several key hurdles to clear before the drugs can become the blockbusters the companies are predicting. Analysts debate how long it will take it will take to overcome these obstacles.

Predicting the Success of HPV Vaccines

Will vaccines against cervical cancer be the blockbusters that Merck and GSK are predicting? Or will issues of cost-effectiveness and parental reluctance hold them back? The experts weigh in on the debate.

When FDA’s Blood Products Advisory Committee meets next week, it is expected to offer crucial insight about the necessary steps for moving an HIV test to over-the-counter status, a subject of debate of at least 10 years.

    OraSure Technologies Inc. wants to make its OraQuick Advance, which screens for HIV strains 1 and 2, available for people to test themselves at home. The company is hoping the committee will provide insight on what it would look for if OraSure submitted an application for over-the-counter status.

    “We are eager to hear their views,” said Douglas Michels, company president and chief executive officer.

    The 20-minute OraQuick test, which involves swabbing the gums with a pad that binds HIV antibodies in saliva, was approved for clinical use in March 2004. An earlier OraSure product that detected only one strain of HIV was approved in 2002.

FDA has discussed over-the-counter HIV diagnostic techniques on several previous occasions, starting in 1998. In 1996 it approved a home collection kit manufactured by Direct Access Diagnostics, a Johnson & Johnson subsidiary, which allowed people to send blood samples through the mail for testing and receive their results over the phone. Other similar collection kits were approved later.

    But OraSure wants to make HIV test results available at home as quickly as they are in a medical office.

    “We’re not seeing a decline in the infection rate, despite the fact that there are more screening programs today than ever,” Michels said. “We’d love to see a day where everyone know their HIV status.”

    Freya Spielberg, co-coodinator of prevention interventions at University of Washington’s Center for AIDS Research and assistant professor of family medicine, said at-home testing is the next step in decreasing the infection rate. She said that 200,000 to 300,000 people in the United States are infected without knowing their status and she believes allowing people to test themselves will decrease this number.

“It’s clear that we need a new strategy to diagnose HIV,” she said.

    At-home rapid tests would be especially beneficial for people without health insurance or those who feel that there is a stigma attached to getting tested, she said.

Based on previous discussions of home testing, and approval of the home collection kits, the advisory committee will likely raise a number of issues.

First, the manufacturer would have to demonstrate that people could use the test correctly and obtain accurate results. (For its 2004 approval, the test demonstrated greater than 99 percent accuracy at predicting HIV infection).

 Michels noted that OraSure has already conducted trials in which participants administered the test on themselves. Moreover, in June 2004 FDA allowed the OraQuick Advance test to be administered in non-laboratory settings, such as doctors’ offices and public health clinics under a waiver from the Clinical Laboratory Improvement Amendments that regulate non-research human testing.

But the company will probably have to design further trials and prove that home tests are as accurate as those given in clinical settings.

    OraSure is “looking to FDA for guidance on what additional proof they might need,” Michels said.

The company would also have to provide adequate resources for people with positive test results, including counseling and medical referrals, Spielberg said. She suggested a 24-hour hotline to provide these services, in addition to an informational Web site.

    The company believes it’s essential that users know, when they purchase the product, how to access help for using the test, interpreting results, and finding appropriate care, Michels said. He noted that rapid test results are preliminary, and it will be necessary for those who test positive to understand that they must confirm the results with a medical caregiver. Michels added that pre- and post-test counseling would be available to users.

    An assessment of the home collection kits, which were approved in 1996, in the Nov. 18, 1998 issue of Journal of the American Medical Association, found the majority of people who tested positive after using these kits accepted referrals. According to data analyzed by Bernard Branson, of the Centers for Disease Control, 65 percent of people who tested positive accepted medical referrals. An additional 23 percent said they had other sources for follow-up medical care. Of the 610 people included in the data one expressed suicidal thoughts.

    According to Spielberg’s research in a group of 240-HIV positive people, 61 percent said they would have preferred to learn their status from an at-home test and more than 80 percent favored making these tests available.

Another issue, Spielberg said, would be making sure people clearly understand the “window period” when HIV can be successfully detected. If people test too soon after they are potentially exposed to the virus, the antibodies will not be detected. As part of the approval process, OraSure will need to demonstrate that people understand this, she said.

    Michels indicated that OraSure would include this type of information in the package. It would also be feature in the product’s public awareness campaign, probably including a Web site.

A look at the issues facing the Blood Products Advisory Committee when it reviews OraSure’s at-home test next month.

Pharmaceutical Executive-10-25-2005

Atypical Antipsychotics Increase Risk of Death for Dementia Patients

Predicting the Success of HPV Vaccines

Predicting the Success of HPV Vaccines

Advisory Committee to Review OTC HIV Test