Drug safety and regulation
http://www.100md.com
《英国医生杂志》
New powers and resources are needed
In the past few months, medical journals have published numerous editorials and news items relating to drug safety and regulation.1-3 The withdrawal of rofecoxib (Vioxx) has been the single biggest issue,4 but the cardiovascular safety of other cyclo-oxygenase-2 (COX 2) inhibitors5 and possible suicidal tendencies associated with selective serotonin reuptake inhibitor (SSRI) antidepressants have also raised considerable concerns.6 These high profile cases have resulted in the regulatory bodies responsible for drug safety coming under fire.
From reports in journals it would be easy to get the impression that the US Food and Drug Administration was uniquely at fault over the regulation of COX 2 inhibitors7 and the UK Medicines and Healthcare products Regulatory Agency over paroxetine.3 Given that the regulatory decisions made before and after the marketing of these drugs have been similar throughout the developed world, this can hardly be a logical conclusion. Overall, regulators around the world use similar systems and make similar decisions. If they all get something wrong then it is probably the fault of inadequacies in the underlying systems and, perhaps, the science underpinning them.
We have been, and are, involved with drug regulation in the United Kingdom. We believe that the whole safety system for drugs might be improved, going well beyond the processes of regulation itself. For example, the pharmaceutical industry clearly has an important role, although the extent and nature of its influence have recently been called into question.8 It is important to keep a perspective on where the existing system has come from, how it developed, and where it is going. The current system began a little over 40 years ago in the wake of the thalidomide disaster. Although it has continued to evolve gradually, the basic principles and powers laid down in the 1960s have not changed, and adverse drug reactions remain an important cause of morbidity and mortality.9
Drug usage can be made safer through advances in safety science. A model for excellence in pharmacovigilance has been proposed,10 and some principles from that have gained widespread acceptance—for example, the development of safety specifications and pharmacovigilance plans for enhanced surveillance and reporting of drug related harms. These principles, which will become legal requirements in the European Union later this year, focus particularly on how knowledge on the safety of new drugs can be extended after marketing.
There is already an international guideline that is based on these principles, produced by the International Conference on Harmonisation,11 a body that brings together government regulators and drug industry representatives from the United States, the European Union, and Japan to make international drug regulatory processes more efficient and uniform. The International Society for Pharmacoepidemiology, which provides a forum for the open exchange of scientific information and for the development of policy, education, and advocacy in this field, has also considered these issues and proposed ways to increase safety.12
The success of these improvements depends on the strategic coordination of such work and the necessary political support to make things happen. Drug safety, however, is a political graveyard. The priority afforded to this issue and the powers available to enforce it have advanced very little in the past few decades, and influential politicians who might have championed the cause have been conspicuously absent from the debate. Political pressures exist to restrain public expenditure and reduce regulation in health care generally, but if the goal is greater safety through more effective regulation then politicians should understand that new powers and resources will be more important than focusing on the effectiveness of regulators, looking for new people to do the job, and proposing yet more organisational change.
In particular, although clear separation is sensible between people responsible for licensing medicines and those responsible for monitoring postmarketing safety, the case for completely separate (and therefore new) agencies has yet to be made. It would be more logical to rethink the regulatory powers underpinning postmarketing safety of drugs: these were enshrined in law in the 1960s and have advanced little since.
Furthermore, policymakers and politicians internationally focus too much on the efficacy and cost effectiveness of medicines at the expense of safety. It is now time to grasp the nettle, improve the evidence base on harms, and focus on regulating safety to at least an equal extent.
Patrick C Waller, consultant in pharmacoepidemiology
Patrick Waller Limited, Southampton SO30 2NY (patrick.waller@btinternet.com)
Stephen J W Evans, professor of pharmacoepidemiology
London School of Hygiene and Tropical Medicine, London WC1E 7HT
Keith Beard, consultant physician
Victoria Infirmary, Glasgow G42 9TY
Competing interests: PCW was an employee of the UK Medicines Control Agency (MCA) in 1990-2002 and currently holds a contract to consult for the Medicines and Healthcare products Regulatory Agency (MHRA). SJWE was an employee of the UK MCA in 1995-9 and 2000-2 and currently consults for the MHRA. SJWE is a member of the Committee on Safety of Medicines (CSM) working groups on hormone replacement therapy and cyclo-oxygenase-2 (COX 2) inhibitors. SJWE has also been an adviser to the European Medicines Agency on various safety issues. KB is a member of the CSM Sub-Committee on Pharmacovigilance, and of the CSM Working Groups on Patient Information and on COX-2 inhibitors. KB received a single, non-personal lecture fee from Aventis in 2003 and travel expenses from Novartis Consumer Health SA in 2000 to attend one meeting of an expert working group.
References
Horton R. Vioxx, the implosion of Merck, and aftershocks at the FDA. Lancet 2004;364: 1995-6.
Vioxx: lessons for Health Canada and the FDA. CMAJ 2005;172: 5.
Abbasi K. Is drug regulation failing? BMJ 2004; 329.
Lenzer J. FDA is incapable of protecting US "against another Vioxx." BMJ 2004;329: 1253.
Drazen, JM. COX-2 inhibitors—a lesson in unexpected problems. N Engl J Med 2005;352: 1131-2.
Cipriani A, Barbui C, Geddes JR. Suicide, depression, and antidepressants. BMJ 2005;330: 373-4.
Horton R. Safety concerns at the FDA. Lancet 2005;365: 727-8.
Ferner RE. The influence of big pharma. BMJ 2005;330: 855-6.
Pirmohamed M, James S, Meakin S, Green C, Scott AK, Walley TJ, et al. Adverse drug reactions as a cause of admission to hospital: prospective analysis of 18 820 patients. BMJ 2004;329: 15-9.
Waller PC, Evans SJW. A model for the future conduct of pharmacovigilance. Pharmacoepidemiol Drug Safety 2003;12: 17-29.
International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH Harmonised Tripartite Guideline E2E. Pharmacovigilance planning. www.ich.org/MediaServer.jser?@_ID=1195&@_MODE=GLB (accessed 6 May 2005).
International Society for Pharmacoepidemiology. Statement on regulatory systems to improve pharmaceutical safety. Bethesda, MD: ISPE, 2005. www.pharmacoepi.org/resources/regstatement0205.pdf (accessed 5 May 2005).
In the past few months, medical journals have published numerous editorials and news items relating to drug safety and regulation.1-3 The withdrawal of rofecoxib (Vioxx) has been the single biggest issue,4 but the cardiovascular safety of other cyclo-oxygenase-2 (COX 2) inhibitors5 and possible suicidal tendencies associated with selective serotonin reuptake inhibitor (SSRI) antidepressants have also raised considerable concerns.6 These high profile cases have resulted in the regulatory bodies responsible for drug safety coming under fire.
From reports in journals it would be easy to get the impression that the US Food and Drug Administration was uniquely at fault over the regulation of COX 2 inhibitors7 and the UK Medicines and Healthcare products Regulatory Agency over paroxetine.3 Given that the regulatory decisions made before and after the marketing of these drugs have been similar throughout the developed world, this can hardly be a logical conclusion. Overall, regulators around the world use similar systems and make similar decisions. If they all get something wrong then it is probably the fault of inadequacies in the underlying systems and, perhaps, the science underpinning them.
We have been, and are, involved with drug regulation in the United Kingdom. We believe that the whole safety system for drugs might be improved, going well beyond the processes of regulation itself. For example, the pharmaceutical industry clearly has an important role, although the extent and nature of its influence have recently been called into question.8 It is important to keep a perspective on where the existing system has come from, how it developed, and where it is going. The current system began a little over 40 years ago in the wake of the thalidomide disaster. Although it has continued to evolve gradually, the basic principles and powers laid down in the 1960s have not changed, and adverse drug reactions remain an important cause of morbidity and mortality.9
Drug usage can be made safer through advances in safety science. A model for excellence in pharmacovigilance has been proposed,10 and some principles from that have gained widespread acceptance—for example, the development of safety specifications and pharmacovigilance plans for enhanced surveillance and reporting of drug related harms. These principles, which will become legal requirements in the European Union later this year, focus particularly on how knowledge on the safety of new drugs can be extended after marketing.
There is already an international guideline that is based on these principles, produced by the International Conference on Harmonisation,11 a body that brings together government regulators and drug industry representatives from the United States, the European Union, and Japan to make international drug regulatory processes more efficient and uniform. The International Society for Pharmacoepidemiology, which provides a forum for the open exchange of scientific information and for the development of policy, education, and advocacy in this field, has also considered these issues and proposed ways to increase safety.12
The success of these improvements depends on the strategic coordination of such work and the necessary political support to make things happen. Drug safety, however, is a political graveyard. The priority afforded to this issue and the powers available to enforce it have advanced very little in the past few decades, and influential politicians who might have championed the cause have been conspicuously absent from the debate. Political pressures exist to restrain public expenditure and reduce regulation in health care generally, but if the goal is greater safety through more effective regulation then politicians should understand that new powers and resources will be more important than focusing on the effectiveness of regulators, looking for new people to do the job, and proposing yet more organisational change.
In particular, although clear separation is sensible between people responsible for licensing medicines and those responsible for monitoring postmarketing safety, the case for completely separate (and therefore new) agencies has yet to be made. It would be more logical to rethink the regulatory powers underpinning postmarketing safety of drugs: these were enshrined in law in the 1960s and have advanced little since.
Furthermore, policymakers and politicians internationally focus too much on the efficacy and cost effectiveness of medicines at the expense of safety. It is now time to grasp the nettle, improve the evidence base on harms, and focus on regulating safety to at least an equal extent.
Patrick C Waller, consultant in pharmacoepidemiology
Patrick Waller Limited, Southampton SO30 2NY (patrick.waller@btinternet.com)
Stephen J W Evans, professor of pharmacoepidemiology
London School of Hygiene and Tropical Medicine, London WC1E 7HT
Keith Beard, consultant physician
Victoria Infirmary, Glasgow G42 9TY
Competing interests: PCW was an employee of the UK Medicines Control Agency (MCA) in 1990-2002 and currently holds a contract to consult for the Medicines and Healthcare products Regulatory Agency (MHRA). SJWE was an employee of the UK MCA in 1995-9 and 2000-2 and currently consults for the MHRA. SJWE is a member of the Committee on Safety of Medicines (CSM) working groups on hormone replacement therapy and cyclo-oxygenase-2 (COX 2) inhibitors. SJWE has also been an adviser to the European Medicines Agency on various safety issues. KB is a member of the CSM Sub-Committee on Pharmacovigilance, and of the CSM Working Groups on Patient Information and on COX-2 inhibitors. KB received a single, non-personal lecture fee from Aventis in 2003 and travel expenses from Novartis Consumer Health SA in 2000 to attend one meeting of an expert working group.
References
Horton R. Vioxx, the implosion of Merck, and aftershocks at the FDA. Lancet 2004;364: 1995-6.
Vioxx: lessons for Health Canada and the FDA. CMAJ 2005;172: 5.
Abbasi K. Is drug regulation failing? BMJ 2004; 329.
Lenzer J. FDA is incapable of protecting US "against another Vioxx." BMJ 2004;329: 1253.
Drazen, JM. COX-2 inhibitors—a lesson in unexpected problems. N Engl J Med 2005;352: 1131-2.
Cipriani A, Barbui C, Geddes JR. Suicide, depression, and antidepressants. BMJ 2005;330: 373-4.
Horton R. Safety concerns at the FDA. Lancet 2005;365: 727-8.
Ferner RE. The influence of big pharma. BMJ 2005;330: 855-6.
Pirmohamed M, James S, Meakin S, Green C, Scott AK, Walley TJ, et al. Adverse drug reactions as a cause of admission to hospital: prospective analysis of 18 820 patients. BMJ 2004;329: 15-9.
Waller PC, Evans SJW. A model for the future conduct of pharmacovigilance. Pharmacoepidemiol Drug Safety 2003;12: 17-29.
International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH Harmonised Tripartite Guideline E2E. Pharmacovigilance planning. www.ich.org/MediaServer.jser?@_ID=1195&@_MODE=GLB (accessed 6 May 2005).
International Society for Pharmacoepidemiology. Statement on regulatory systems to improve pharmaceutical safety. Bethesda, MD: ISPE, 2005. www.pharmacoepi.org/resources/regstatement0205.pdf (accessed 5 May 2005).