Dilemma over Drug Safety

Drug manufacturers, wary of mass lawsuits like those stemming from fen-phen use, are pulling drugs from the market much sooner than they often did in the past. Federal and state governments and various pharmaceutical industry players are also responding to this movement in surprising ways, given their past apparent tolerance for less-than-perfect disclosure to consumers.

FDA Proposes New Drug Safety Board

On Feb. 15, Health and Human Services Secretary Mike Leavitt and Acting Food and Drug Administration Commissioner Lester M. Crawford announced that the FDA would create a new independent Drug Safety Oversight Board (DSB) to manage drug safety issues. The new agency will be charged with providing information to health care providers and patients about the risks and benefits of medicines. Leavitt told FDA employees at a Feb. 15 meeting, “The public has spoken and they want more oversight and openness. They want to know what we know, what we do with the information and why we do it. We will address their concerns by cultivating openness and enhanced independence.” Until now, one of the primary sources for information about adverse effects of FDA-approved drugs has been the manufacturers themselves who, for obvious reasons, are often reluctant to share bad news with the public.

The specific proposals to improve the way the FDA manages drug safety information focus on making the agency's review and decision-making processes more independent and transparent. To do this, a new entity, the Drug Safety Oversight Board (DSB), will be created to oversee the management of drug safety issues within the Center for Drug Evaluation and Research (CDER). The DSB, whose members will be appointed by the FDA Commissioner, is expected to consult with other medical experts and representatives of patient and consumer groups when making decisions.

As part of its plan for greater agency transparency, the FDA is proposing a new Drug Watch Web page that will include emerging information for both previously and newly approved drugs. The site will tell the public about possible serious side effects or other safety risks that have the potential to alter the benefit/risk analysis of a drug, affect patient selection or monitoring decisions, or that can be avoided through measures taken to prevent or mitigate harm.

The FDA also plans to direct better product labeling that will include new information about medications when it becomes available, based on adverse event reports. In addition, the agency will increase the use of consumer-friendly information sheets written especially for health care professionals and patients.

Critics of the FDA plan fear the DSB will not have adequate power or be independent enough to effect any significant change in the status quo. It will be closely aligned with the FDA, in large part because its members will be appointed by the FDA's Commissioner. In addition, the DSB will be funded from existing appropriations, although a greater appropriation may be made in future years. Thus, it is unclear whether the increased funds that would undoubtedly be needed to gather information from multiple sources and to conduct in-depth research will be available to the new panel.

Clinical Trial Transparency

Another reform movement from outside the pharmaceutical research community gained momentum last year and has led to sweeping changes in what drug developers report to the public about their clinical trial findings.

One impetus for the movement came from consumer outrage over undisclosed unfavorable results in tests of Paxil', an antidepressant manufactured by GlaxoSmithKline. GlaxoSmithKline had published test results that showed Paxil's advantages in treating depression, but did not disclose certain problems that could develop when taking the drug. Some of those unfavorable test results came to light when a researcher who had worked on the development of the drug disclosed them at a conference. When British regulators last year asked for and received unpublished test findings for several antidepressants, they got the full story. The British conclusion: Drug manufacturers had evidence that antidepressants could cause suicidal ideation in children and adolescents, but they had failed to clue the public in to these findings. When this information was finally disclosed, it of course caused a good deal of consternation in the medical world, with parents and medical practitioners questioning the wisdom of giving youngsters such medications at all. Members of the public began to ask the question: What else are drug companies keeping from us? At least one state government stepped into the fight:

New York's attorney general, Eliot Spitzer, filed suit in Manhattan seeking compensation for the “fraud” GlaxoSmithKline allegedly perpetrated against New York doctors and patients by selectively revealing favorable information and hiding unfavorable test results that would have alerted the public to the dangers young people faced in taking Paxil.

Regulators and consumers were not the only ones calling for more information about clinical trial findings. In June 2004, the International Committee of Medical Journal Editors (ICMJE) first proposed requiring drug manufacturers to register all clinical trials in an international database before beginning tests. The purpose of the registry would be to force drug developers to disclose the results of all tests, not just those that would tend to make a drug more commercially viable. The ICMJE, made up of 12 prestigious member publications, including The New England Journal of Medicine and British medical journal The Lancet, would, under the proposed plan, decline to publish study results concerning pharmaceutical products whose research plans were not pre-registered and followed up with in the database. Drug researchers might still be able to get their studies published in other medical journals, but the publications represented in the ICMJE are some of the most prestigious in the world and publication in them is considered a powerful marketing tool.

At the American Medical Association's annual meeting in June 2004, the association's members adopted a resolution calling for the federal government to set up a database for drug trial registration. The AMA's doctors' move was another expression of the new demand for the full information on test results that would help them make the best decisions for their patients' health. On March 1 of this year, Senate Finance Committee Chair Chuck Grassley (R-IA) began the process of enacting legislation that does just what the AMA wants. He and several Democratic legislators introduced a bill that calls for a new database that will contain information about clinical trials including their outcomes, potential side effects, funding sources and participant demographic information.

Industry Reaction

In response to all this reform momentum, the Executive Committee of the Pharmaceutical Research and Manufacturers (PhRMA), the trade group representing pharmaceutical manufacturers, unanimously adopted a set of principles for the conduct of clinical trials and the communication of results of clinical trials. The resolution, announced last year, calls for PhRma member companies and others involved in clinical research to conduct trials according to a set of principles, including these: 1) Clinical trials should be conducted in accordance with Good Clinical Practice, no matter where in the world the trials take place; 2) Clinical investigators should be independent and should be reasonably compensated, but not with stock from the trial's sponsor; 3) Clinical trials should be reviewed by Institution of Review Boards or Ethics Committees before they are begun; 4) Clinical trial participants should give their informed consent before taking part in clinical studies; 5) Study results should be timely reported, whether favorable or unfavorable, and in an unbiased manner; 6) Study sponsors should not suppress publication of results; and 7) Only those who make substantial contributions to the clinical trial should be given authorship credit in publications of the results.

Although PhRMA asserted at the time it promulgated these rules that adherence to ethics rules similar to these has been the norm for most pharmaceutical companies, its Executive Committee was moved to set these principles down in one place in order to restore confidence in the clinical trial process. The PhRMA principles are voluntary only and not binding on PhRMA member companies, but the pressures of public opinion may force substantial compliance.

Cost/Benefit Analyses

The bottom line is that medical practitioners and consumers want and require as much information as possible so that they can make educated decisions about which drugs and treatments to employ.

On March 1, before a Senate panel, the FDA's deputy director of the office of new drugs even admitted that the agency had probably not done enough to let the public know about the dangers of Vioxx', a Cox-2 inhibitor that was voluntarily pulled from the market long after its manufacturer knew that it could double certain patients' risk of heart attack and stroke. Just days after the FDA announced it would create its new drug oversight board, a panel of doctors and scientists held a three-day forum to discuss the question of whether Cox-2 inhibitors like Vioxx, Celebrex' and Bextra', which are used to treat arthritis, should be pulled from the market. Their recommendation was that these drugs should not be banned, but that they should be sold with stronger warning labels.

Conclusion

Perhaps this is all the public and medical profession require: the fullest information possible with which to make medical decisions. Although doctors would like to be able to guarantee a good result to their patients when prescribing a medication, it is obvious that this goal can't be met. No drug is perfectly safe for all who may take it. However, with the evolving transparency movements pushing for reforms, the increased availability of all pertinent information should lead to increased confidence in pharmaceutical products and in the health care providers who prescribe them.

There is a newly urgent push from outside the pharmaceutical research and development community to get drug firms and the government to disclose the results of all tests conducted on new drugs and to immediately reveal information about problems that develop after those drugs go on the market. Consumers and health care providers say they're tired of finding out belatedly that negative information has come to light about the drugs they take or prescribe.

Of course, the Food and Drug Administration (FDA) has for years been looking out for the public by requiring extensive testing of all new drugs before they can be placed on the market, but critics charge that the agency, being intimately tied to the very industry it is policing, has not done enough. High on the list of concerns is the fact that after a drug is approved, its effects on consumers are not generally studied at present.

Consumer advocates have taken up the slack they see in the FDA's oversight of the drug manufacturing industry. For example, consumer group Public Citizen recently announced it had launched an updated Web site, www.WorstPills.org, to provide consumers with information about drugs the group considers unsafe or ineffective. The group, whose drug information Web site is accessible by subscription, claims that nearly 200 drugs on the market today are unsafe or ineffective.

Drug manufacturers, wary of mass lawsuits like those stemming from fen-phen use, are pulling drugs from the market much sooner than they often did in the past. Federal and state governments and various pharmaceutical industry players are also responding to this movement in surprising ways, given their past apparent tolerance for less-than-perfect disclosure to consumers.

FDA Proposes New Drug Safety Board

On Feb. 15, Health and Human Services Secretary Mike Leavitt and Acting Food and Drug Administration Commissioner Lester M. Crawford announced that the FDA would create a new independent Drug Safety Oversight Board (DSB) to manage drug safety issues. The new agency will be charged with providing information to health care providers and patients about the risks and benefits of medicines. Leavitt told FDA employees at a Feb. 15 meeting, “The public has spoken and they want more oversight and openness. They want to know what we know, what we do with the information and why we do it. We will address their concerns by cultivating openness and enhanced independence.” Until now, one of the primary sources for information about adverse effects of FDA-approved drugs has been the manufacturers themselves who, for obvious reasons, are often reluctant to share bad news with the public.

The specific proposals to improve the way the FDA manages drug safety information focus on making the agency's review and decision-making processes more independent and transparent. To do this, a new entity, the Drug Safety Oversight Board (DSB), will be created to oversee the management of drug safety issues within the Center for Drug Evaluation and Research (CDER). The DSB, whose members will be appointed by the FDA Commissioner, is expected to consult with other medical experts and representatives of patient and consumer groups when making decisions.

As part of its plan for greater agency transparency, the FDA is proposing a new Drug Watch Web page that will include emerging information for both previously and newly approved drugs. The site will tell the public about possible serious side effects or other safety risks that have the potential to alter the benefit/risk analysis of a drug, affect patient selection or monitoring decisions, or that can be avoided through measures taken to prevent or mitigate harm.

The FDA also plans to direct better product labeling that will include new information about medications when it becomes available, based on adverse event reports. In addition, the agency will increase the use of consumer-friendly information sheets written especially for health care professionals and patients.

Critics of the FDA plan fear the DSB will not have adequate power or be independent enough to effect any significant change in the status quo. It will be closely aligned with the FDA, in large part because its members will be appointed by the FDA's Commissioner. In addition, the DSB will be funded from existing appropriations, although a greater appropriation may be made in future years. Thus, it is unclear whether the increased funds that would undoubtedly be needed to gather information from multiple sources and to conduct in-depth research will be available to the new panel.

Clinical Trial Transparency

Another reform movement from outside the pharmaceutical research community gained momentum last year and has led to sweeping changes in what drug developers report to the public about their clinical trial findings.

One impetus for the movement came from consumer outrage over undisclosed unfavorable results in tests of Paxil', an antidepressant manufactured by GlaxoSmithKline. GlaxoSmithKline had published test results that showed Paxil's advantages in treating depression, but did not disclose certain problems that could develop when taking the drug. Some of those unfavorable test results came to light when a researcher who had worked on the development of the drug disclosed them at a conference. When British regulators last year asked for and received unpublished test findings for several antidepressants, they got the full story. The British conclusion: Drug manufacturers had evidence that antidepressants could cause suicidal ideation in children and adolescents, but they had failed to clue the public in to these findings. When this information was finally disclosed, it of course caused a good deal of consternation in the medical world, with parents and medical practitioners questioning the wisdom of giving youngsters such medications at all. Members of the public began to ask the question: What else are drug companies keeping from us? At least one state government stepped into the fight:

New York's attorney general, Eliot Spitzer, filed suit in Manhattan seeking compensation for the “fraud” GlaxoSmithKline allegedly perpetrated against New York doctors and patients by selectively revealing favorable information and hiding unfavorable test results that would have alerted the public to the dangers young people faced in taking Paxil.

Regulators and consumers were not the only ones calling for more information about clinical trial findings. In June 2004, the International Committee of Medical Journal Editors (ICMJE) first proposed requiring drug manufacturers to register all clinical trials in an international database before beginning tests. The purpose of the registry would be to force drug developers to disclose the results of all tests, not just those that would tend to make a drug more commercially viable. The ICMJE, made up of 12 prestigious member publications, including The New England Journal of Medicine and British medical journal The Lancet, would, under the proposed plan, decline to publish study results concerning pharmaceutical products whose research plans were not pre-registered and followed up with in the database. Drug researchers might still be able to get their studies published in other medical journals, but the publications represented in the ICMJE are some of the most prestigious in the world and publication in them is considered a powerful marketing tool.

At the American Medical Association's annual meeting in June 2004, the association's members adopted a resolution calling for the federal government to set up a database for drug trial registration. The AMA's doctors' move was another expression of the new demand for the full information on test results that would help them make the best decisions for their patients' health. On March 1 of this year, Senate Finance Committee Chair Chuck Grassley (R-IA) began the process of enacting legislation that does just what the AMA wants. He and several Democratic legislators introduced a bill that calls for a new database that will contain information about clinical trials including their outcomes, potential side effects, funding sources and participant demographic information.

Industry Reaction

In response to all this reform momentum, the Executive Committee of the Pharmaceutical Research and Manufacturers (PhRMA), the trade group representing pharmaceutical manufacturers, unanimously adopted a set of principles for the conduct of clinical trials and the communication of results of clinical trials. The resolution, announced last year, calls for PhRma member companies and others involved in clinical research to conduct trials according to a set of principles, including these: 1) Clinical trials should be conducted in accordance with Good Clinical Practice, no matter where in the world the trials take place; 2) Clinical investigators should be independent and should be reasonably compensated, but not with stock from the trial's sponsor; 3) Clinical trials should be reviewed by Institution of Review Boards or Ethics Committees before they are begun; 4) Clinical trial participants should give their informed consent before taking part in clinical studies; 5) Study results should be timely reported, whether favorable or unfavorable, and in an unbiased manner; 6) Study sponsors should not suppress publication of results; and 7) Only those who make substantial contributions to the clinical trial should be given authorship credit in publications of the results.

Although PhRMA asserted at the time it promulgated these rules that adherence to ethics rules similar to these has been the norm for most pharmaceutical companies, its Executive Committee was moved to set these principles down in one place in order to restore confidence in the clinical trial process. The PhRMA principles are voluntary only and not binding on PhRMA member companies, but the pressures of public opinion may force substantial compliance.

Cost/Benefit Analyses

The bottom line is that medical practitioners and consumers want and require as much information as possible so that they can make educated decisions about which drugs and treatments to employ.

On March 1, before a Senate panel, the FDA's deputy director of the office of new drugs even admitted that the agency had probably not done enough to let the public know about the dangers of Vioxx', a Cox-2 inhibitor that was voluntarily pulled from the market long after its manufacturer knew that it could double certain patients' risk of heart attack and stroke. Just days after the FDA announced it would create its new drug oversight board, a panel of doctors and scientists held a three-day forum to discuss the question of whether Cox-2 inhibitors like Vioxx, Celebrex' and Bextra', which are used to treat arthritis, should be pulled from the market. Their recommendation was that these drugs should not be banned, but that they should be sold with stronger warning labels.

Conclusion

Perhaps this is all the public and medical profession require: the fullest information possible with which to make medical decisions. Although doctors would like to be able to guarantee a good result to their patients when prescribing a medication, it is obvious that this goal can't be met. No drug is perfectly safe for all who may take it. However, with the evolving transparency movements pushing for reforms, the increased availability of all pertinent information should lead to increased confidence in pharmaceutical products and in the health care providers who prescribe them.