Torcetrapib and Atorvastatin
http://www.100md.com
《新英格兰医药杂志》
To the Editor: Avorn's proposal in his Perspective article (June 23 issue)1 that the combination of torcetrapib and atorvastatin is market-driven, undermining its usefulness, is baseless. The program does not extend the patent on atorvastatin. Its basic aim is to provide efficiently the greatest medical benefit to the most patients while maintaining the greatest likelihood of success.
Mandatory control of low-density lipoprotein (LDL) cholesterol is a foundation of treatment for patients who are at increased risk for heart disease, including those with isolated low levels of high-density lipoprotein (HDL) cholesterol.2 Torcetrapib alone at the dose used in phase 3 studies does not provide sufficient reduction of the LDL cholesterol level. Therefore, researchers cannot ethically study torcetrapib alone. Combining it with atorvastatin, a safe and effective statin,3 will provide the needed control of LDL cholesterol.
Early clinical data from a phase 2 study showed that torcetrapib alone causes highly variable changes in LDL cholesterol levels, including notable increases, in patients with triglyceride levels of 150 mg per deciliter (1.69 mmol per liter) or higher. Combining torcetrapib with atorvastatin eliminated this variance, implying that robust lowering of triglyceride levels is an important component of treatment. Pfizer saw this finding as reinforcing the need for atorvastatin as the concurrent treatment, given its triglyceride-lowering advantage over other statins.4
The hypothesis that torcetrapib–atorvastatin will ultimately benefit patients by raising HDL cholesterol levels and incrementally lowering LDL cholesterol levels remains to be proven. The regulatory hurdles for approval are clear: unambiguous demonstration of an efficacy benefit over atorvastatin alone, including lipid and vascular benefits, along with documentation of safety.5 Recognition of these hurdles solidified the need to use a single statin in the initial development program. It allows valid hypothesis testing by keeping the statin effect constant. The "all comers" approach that has been suggested opens trial results to important potential biases and ambiguities, since all the marketed statins have different efficacy and safety profiles. Regulatory approval requires unambiguous results. The single torcetrapib–atorvastatin product will also enhance long-term patient compliance and affordability.6 Avorn's concern about high cost is without merit. We do not yet have a clinical profile to inform pricing.
Charles L. Shear, Dr.P.H.
Pfizer Global Research and Development
New London, CT 06320
References
Avorn J. Torcetrapib and atorvastatin -- should marketing drive the research agenda? N Engl J Med 2005;352:2573-2576.
Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. Circulation 2004;110:227-239.
van Leuven SI, Kastelein JJP. Atorvastatin. Expert Opin Pharmacother 2005;6:1191-1203.
Ballantyne CM, Andrews TC, Hsia JA, Kramer JH, Shear C, ACCESS Study Group. Correlation of non-high-density lipoprotein cholesterol with apolipoprotein B: effect of 5 hydroxymethylglutaryl coenzyme A reductase inhibitors on non-high-density lipoprotein cholesterol levels. Am J Cardiol 2001;88:265-269.
Issaacsohn JL, Troendle AJ, Orloff DG. Regulatory issues in the approval of new drugs for diabetes mellitus, dyslipidemia, and the metabolic syndrome. Am J Cardiol 2004;93:49C-52C.
Leichter SB, Thomas S. Combination medications in diabetes care: an opportunity that merits more attention. Clinical Diabetes 2003;21:175-8.
To the Editor: Avorn's Perspective article is eye-opening. It seems unconscionable for Pfizer to put corporate profit above the health benefit that this drug could provide.
In 2004, a group of physicians who treat patients with human immunodeficiency virus (HIV) infection called for a boycott of all Abbott products in response to a 400 percent price increase for ritonavir. Rather than stop prescribing ritonavir, we stopped using clarithromycin (Biaxin), levothyroxine (Synthroid), cefdinir (Omnicef), and other Abbott medications. We also banned Abbott representatives from our offices. In response, Abbott made substantial concessions in its pricing structure.
It seems appropriate that Pfizer's plan for torcetrapib be met with a boycott of Pfizer's products and activities. There are many brand-name and generic alternatives to most of the medications sold by Pfizer. Moreover, most physicians will not miss the interruptions of their office flow by Pfizer sales representatives. If a few hundred HIV physicians could convince Abbott to reassess its pricing structure, imagine the effect of thousands of primary care physicians, cardiologists, and endocrinologists on Pfizer's plans for studying and marketing torcetrapib.
Ronald L. Hirsch, M.D.
Signature Medical Associates
Elgin, IL 60123
rhirsch@signaturedoctors.com
To the Editor: In 1984, the Hatch–Waxman Act amended U.S. patent laws to provide the right for others to make use of the subject matter of valid patents for purposes "reasonably related" to the approvals of generic copies of original drugs.
Thus, under Hatch–Waxman, if torcetrapib is successfully brought to market, others can manufacture a copy to gain information about its safety and efficacy alone or in combination with other statins. If such studies provided important new public health information about safety and efficacy, the Food and Drug Administration would arguably have grounds for requesting that the patent holder perform additional safety studies.
Who would pay for such studies if patents for torcetrapib have many years to run? Presumably, it would be in the interests of health care payers and manufacturers of generic drugs to share the costs if they had sizable economic concerns. Nonprofit organizations might take on such costs if important questions of clinical care were believed by some to be unresolved by the original sponsor's studies.
Allan M. Green, M.D., J.D.
124 Mt. Auburn St.
Cambridge, MA 02138
amgreen@fdaregs.com
Dr. Avorn replies: Dr. Shear contends that Pfizer's decision to study its HDL cholesterol–lowering drug torcetrapib only in combination with the company's atorvastatin (Lipitor) will not extend the latter drug's patent life. But if the company uses these trial data to justify manufacturing the new agent only in a fixed combination with Lipitor, such an extension is exactly what the effective result will be. A senior executive has now stated publicly that the company does not intend to use the trials in this coercive way; we will await its marketing plans to see whether Pfizer adheres to this promise and makes torcetrapib available for use by clinicians who choose to combine it with a different LDL cholesterol–lowering drug.
No one has suggested that the company should test torcetrapib as monotherapy for dyslipidemia, since the majority of patients will require concurrent lowering of LDL cholesterol. Dr. Shear writes that Pfizer rejected trial designs that would have allowed the use of other statins purely for the sake of "keeping the statin effect constant," but there are several statins on the market whose track records of safety and efficacy are longer than those of atorvastatin. If scientific parsimony is the only reason for the current study designs, we can assume that once torcetrapib is marketed, Pfizer will make it available as a single agent for use with other established statins as well. But Dr. Shear is already referring to a "single torcetrapib–atorvastatin product" to enhance compliance and affordability. It is hard to see how a marketing plan that prevents the use of a generic statin will enhance affordability, and we know that high price is one of the biggest causes of poor compliance.
Dr. Green raises an interesting point about the rights of others to perform research on a patented product. However, we do not have a well-functioning infrastructure for performing such public-interest drug trials, even if doing so could generate clinically important findings and save hundreds of millions of dollars for payers inside and outside of government. Even if such trials were completed and showed that torcetrapib worked well with a variety of different statins, the patent laws would prevent anyone but Pfizer from selling it until its patent expired. The latter restriction is not in itself a problem; we need to have reasonably enforced intellectual-property regulations to protect genuine innovation. But when the patent laws are used in ways that go beyond their original intent, as they would be in the case of a torcetrapib –Lipitor fixed combination, the public's trust in companies' patent rights is undermined. Such abuse of the system is likely to bring about more of the kind of physician backlash that Dr. Hirsch describes.
Jerry Avorn, M.D.
Harvard Medical School
Boston, MA 02115
Mandatory control of low-density lipoprotein (LDL) cholesterol is a foundation of treatment for patients who are at increased risk for heart disease, including those with isolated low levels of high-density lipoprotein (HDL) cholesterol.2 Torcetrapib alone at the dose used in phase 3 studies does not provide sufficient reduction of the LDL cholesterol level. Therefore, researchers cannot ethically study torcetrapib alone. Combining it with atorvastatin, a safe and effective statin,3 will provide the needed control of LDL cholesterol.
Early clinical data from a phase 2 study showed that torcetrapib alone causes highly variable changes in LDL cholesterol levels, including notable increases, in patients with triglyceride levels of 150 mg per deciliter (1.69 mmol per liter) or higher. Combining torcetrapib with atorvastatin eliminated this variance, implying that robust lowering of triglyceride levels is an important component of treatment. Pfizer saw this finding as reinforcing the need for atorvastatin as the concurrent treatment, given its triglyceride-lowering advantage over other statins.4
The hypothesis that torcetrapib–atorvastatin will ultimately benefit patients by raising HDL cholesterol levels and incrementally lowering LDL cholesterol levels remains to be proven. The regulatory hurdles for approval are clear: unambiguous demonstration of an efficacy benefit over atorvastatin alone, including lipid and vascular benefits, along with documentation of safety.5 Recognition of these hurdles solidified the need to use a single statin in the initial development program. It allows valid hypothesis testing by keeping the statin effect constant. The "all comers" approach that has been suggested opens trial results to important potential biases and ambiguities, since all the marketed statins have different efficacy and safety profiles. Regulatory approval requires unambiguous results. The single torcetrapib–atorvastatin product will also enhance long-term patient compliance and affordability.6 Avorn's concern about high cost is without merit. We do not yet have a clinical profile to inform pricing.
Charles L. Shear, Dr.P.H.
Pfizer Global Research and Development
New London, CT 06320
References
Avorn J. Torcetrapib and atorvastatin -- should marketing drive the research agenda? N Engl J Med 2005;352:2573-2576.
Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. Circulation 2004;110:227-239.
van Leuven SI, Kastelein JJP. Atorvastatin. Expert Opin Pharmacother 2005;6:1191-1203.
Ballantyne CM, Andrews TC, Hsia JA, Kramer JH, Shear C, ACCESS Study Group. Correlation of non-high-density lipoprotein cholesterol with apolipoprotein B: effect of 5 hydroxymethylglutaryl coenzyme A reductase inhibitors on non-high-density lipoprotein cholesterol levels. Am J Cardiol 2001;88:265-269.
Issaacsohn JL, Troendle AJ, Orloff DG. Regulatory issues in the approval of new drugs for diabetes mellitus, dyslipidemia, and the metabolic syndrome. Am J Cardiol 2004;93:49C-52C.
Leichter SB, Thomas S. Combination medications in diabetes care: an opportunity that merits more attention. Clinical Diabetes 2003;21:175-8.
To the Editor: Avorn's Perspective article is eye-opening. It seems unconscionable for Pfizer to put corporate profit above the health benefit that this drug could provide.
In 2004, a group of physicians who treat patients with human immunodeficiency virus (HIV) infection called for a boycott of all Abbott products in response to a 400 percent price increase for ritonavir. Rather than stop prescribing ritonavir, we stopped using clarithromycin (Biaxin), levothyroxine (Synthroid), cefdinir (Omnicef), and other Abbott medications. We also banned Abbott representatives from our offices. In response, Abbott made substantial concessions in its pricing structure.
It seems appropriate that Pfizer's plan for torcetrapib be met with a boycott of Pfizer's products and activities. There are many brand-name and generic alternatives to most of the medications sold by Pfizer. Moreover, most physicians will not miss the interruptions of their office flow by Pfizer sales representatives. If a few hundred HIV physicians could convince Abbott to reassess its pricing structure, imagine the effect of thousands of primary care physicians, cardiologists, and endocrinologists on Pfizer's plans for studying and marketing torcetrapib.
Ronald L. Hirsch, M.D.
Signature Medical Associates
Elgin, IL 60123
rhirsch@signaturedoctors.com
To the Editor: In 1984, the Hatch–Waxman Act amended U.S. patent laws to provide the right for others to make use of the subject matter of valid patents for purposes "reasonably related" to the approvals of generic copies of original drugs.
Thus, under Hatch–Waxman, if torcetrapib is successfully brought to market, others can manufacture a copy to gain information about its safety and efficacy alone or in combination with other statins. If such studies provided important new public health information about safety and efficacy, the Food and Drug Administration would arguably have grounds for requesting that the patent holder perform additional safety studies.
Who would pay for such studies if patents for torcetrapib have many years to run? Presumably, it would be in the interests of health care payers and manufacturers of generic drugs to share the costs if they had sizable economic concerns. Nonprofit organizations might take on such costs if important questions of clinical care were believed by some to be unresolved by the original sponsor's studies.
Allan M. Green, M.D., J.D.
124 Mt. Auburn St.
Cambridge, MA 02138
amgreen@fdaregs.com
Dr. Avorn replies: Dr. Shear contends that Pfizer's decision to study its HDL cholesterol–lowering drug torcetrapib only in combination with the company's atorvastatin (Lipitor) will not extend the latter drug's patent life. But if the company uses these trial data to justify manufacturing the new agent only in a fixed combination with Lipitor, such an extension is exactly what the effective result will be. A senior executive has now stated publicly that the company does not intend to use the trials in this coercive way; we will await its marketing plans to see whether Pfizer adheres to this promise and makes torcetrapib available for use by clinicians who choose to combine it with a different LDL cholesterol–lowering drug.
No one has suggested that the company should test torcetrapib as monotherapy for dyslipidemia, since the majority of patients will require concurrent lowering of LDL cholesterol. Dr. Shear writes that Pfizer rejected trial designs that would have allowed the use of other statins purely for the sake of "keeping the statin effect constant," but there are several statins on the market whose track records of safety and efficacy are longer than those of atorvastatin. If scientific parsimony is the only reason for the current study designs, we can assume that once torcetrapib is marketed, Pfizer will make it available as a single agent for use with other established statins as well. But Dr. Shear is already referring to a "single torcetrapib–atorvastatin product" to enhance compliance and affordability. It is hard to see how a marketing plan that prevents the use of a generic statin will enhance affordability, and we know that high price is one of the biggest causes of poor compliance.
Dr. Green raises an interesting point about the rights of others to perform research on a patented product. However, we do not have a well-functioning infrastructure for performing such public-interest drug trials, even if doing so could generate clinically important findings and save hundreds of millions of dollars for payers inside and outside of government. Even if such trials were completed and showed that torcetrapib worked well with a variety of different statins, the patent laws would prevent anyone but Pfizer from selling it until its patent expired. The latter restriction is not in itself a problem; we need to have reasonably enforced intellectual-property regulations to protect genuine innovation. But when the patent laws are used in ways that go beyond their original intent, as they would be in the case of a torcetrapib –Lipitor fixed combination, the public's trust in companies' patent rights is undermined. Such abuse of the system is likely to bring about more of the kind of physician backlash that Dr. Hirsch describes.
Jerry Avorn, M.D.
Harvard Medical School
Boston, MA 02115