- Email: [email protected]
Drug eluting stents and the critical path initiative: Evolving paradigms for safety evaluation
Drug Discovery Today: Technologies
Vol. 4, No. 2 2007
Editors-in-Chief Kelvin Lam – Harvard Stem Cell Institute, Harvard University, USA Henk Timmerman – Vrije Universiteit, The Netherlands DRUG DISCOVERY
TODAY
TECHNOLOGIES
Critical path
Drug eluting stents and the critical path initiative: Evolving paradigms for safety evaluation Wendy R. Sanhai1,*, Norman Stockbridge2, Robert P. Fiorentino3, Takahiro Uchida3, Kathleen Uhl4, Mitch W. Krucoff5 1
Office of the Commissioner, Food and Drug Administration (FDA), Rockville, MD, USA Division of Cardiovascular and Renal Products, Center for Drug Evaluation and Research, FDA, Rockville, MD, USA 3 Division of Cardiovascular Devices, Center for Devices and Radiological Health, FDA, Rockville, MD, USA 4 FDA, Rockville, MD, USA 5 Duke University Medical Center, Cardiovascular Devices Unit, Duke Clinical Research Institute, Durham, NC 27710, USA 2
Recent discussions between FDA and other stakeholders have focused on the benefits and risks associated with drug eluting stents (DES). A particular topic of
Section Editor: Janet Woodcock – Food and Drug Administration, Rockville, MD, USA
focus is DES thrombosis, a rare, but serious, clinical event that may occur months to years after the initial implantation. FDA continues vigilant postmarket surveillance of DES currently on the market and is working with stent manufactures to ensure that new DES platforms in the development pipeline are safe and effective. FDA is also taking steps, under its Critical Path Initiative (CPI) [FDA. Innovation or Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products, March 2004. http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html], to help address current and future DES safety issues. This article describes some of these activities.
Introduction Coronary stents are permanently implanted devices that are placed percutaneously in one or more coronary arteries to *Corresponding author: : W.R. Sanhai ([email protected]), M.W. Krucoff ([email protected]) 1740-6749/$ ß 2007 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.ddtec.2007.10.004
restore and maintain patency. A drug eluting stent (DES) is a combination product, in which a device (coronary stent) incorporates a pharmacologically active agent (drug) that is delivered at the site of stent deployment to reduce neointimal hyperplasia that can cause arterial re-narrowing (restenosis) after percutaneous coronary intervention (PCI). A key component of DES platforms is the polymer or equivalent carrier that can be loaded with drug and is bound to the stent. Properties of this polymer carrier determine how much drug is released and over what period of time, for example, determines dose and kinetics of drug delivery with the intent of preventing smooth muscle cell proliferation and extracelluar matrix synthesis resulting in restenosis. Local cellular reactions to the polymer, however, may occur. DES delivery is accomplished via expanding an inflatable balloon, on which the stent has been mounted or crimped. Balloon inflation deploys the stent against the inner arterial wall and inevitably traumatizes the artery in the locale of deployment. After a DES is implanted, it slowly releases the drug from its stent platform over a period of weeks or months. The major benefit of a DES is that the medication provided 43
Drug Discovery Today: Technologies | Critical path
helps to prevent restenosis, the formation of neointimal, or scar, tissue that reblocks the artery. Additional systemic antiplatelet medications are typically used in patients receiving DES to minimize risk of platelet thrombus formation while the vascular tissue recovers from localized trauma and as endothelium grows over the DES platform. Antiplatelet therapy involves indefinite, daily aspirin therapy combined with a finite course of clopidogrel (or less commonly ticlopidine), which in combination is referred to as dual antiplatelet therapy (DAPT). FDA and stakeholders are continuing to explore the benefits and risks of DES use. Although the efficacy of these combination products is well accepted, there is growing concern that the risk of stent thrombosis, with catastrophic clinical results, such as myocardial infarction (MI) or death, could persist over the lifetime of patients implanted with DES. Particular attention has been given to late stent thrombosis, defined as thrombosis occurring after 1 year postimplantation.
Key technologies Since their introduction, DESs have been implanted in millions of people worldwide with coronary artery disease. These tiny metal mesh tubes, coated with polymer loaded with drugs that inhibit cell reproduction, are designed to re-establish patency in arteries that may have been partially or completely blocked by arteriosclerotic plaque. In current DES, the drug is incorporated into and released from a polymeric coating of sufficient capacity to accommodate the selected dose and to modulate its delivery at the intended site of action and for the intended duration. The chemical, physical and mechanical attributes of the polymer coating system are important for stent deployment, biocompatibility and stability. To date, FDA has approved two DES for commercial distribution – the Cypher-sirolimus DES (Cordis, approved April 24, 2003) and the Taxus-paclitaxel DES (Boston Scientific, approved March 3, 2004) – and believes that, if used as labeled, these medical devices are both safe and effective. However, noting some reports of subacute stent thrombosis (24 h to 30 days post-implant) in one particular DES and recognizing this as a serious adverse event that is sometimes associated with acute MI or sudden death, FDA alerted physicians to these reports in July and October 2003 [2]. FDA concluded there was no evidence to suggest that use of this DES, when implanted in accordance with the approved indications, was associated with an excess of subacute thromboses as compared with bare-metal stents [3]. Of note, subacute stent thrombosis had been previously observed with bare metal stents, prompting treatment with DAPT postimplantation. DAPT is also required for DES clinical trials and is recommended in all relevant medical practice guidelines. 44
www.drugdiscoverytoday.com
Vol. 4, No. 2 2007
FDA has been monitoring the use of coronary DES and associated patient outcomes since they came on the U.S. market in 2003 and 2004 and will continue to do so. Most recently, FDA attention has been drawn to studies suggesting that DES may pose a small but significant risk of late stent thrombosis (after 1-year post-implantation) not observed during premarket studies. The agency is keenly interested in this issue since such events are often associated with serious adverse outcomes for patients. To help address some of these important issues, FDA convened a meeting of its Circulatory System Devices Advisory Panel on December 7 and 8, 2006, to examine the safety of these devices. Some of the major objectives of this Advisory Panel were to obtain consensus from experts and stakeholders in the field to inform FDA’s activities regarding the incidence and timing of stent thrombosis as well as the appropriate duration of DAPT use in patients who receive DES. This panel assisted the agency in the review and analysis of the available scientific data and provided recommendations for appropriate actions to address this issue. Recommendations included possible modification of the device labeling and the need for additional clinical studies. Perspectives following the panel meeting were as follows: Based on data presented from nonrandomized studies, the panel concluded that a more prolonged course of clopidogrel than that recommended in the stent labels (currently 3 months for recipients of the Cypher stent and 6 months for recipients of the Taxus stent) is likely to be beneficial. Nevertheless, stent thrombosis may occur despite continued DAPT. Antiplatelet therapy carries the small risk of hemorrhage, including strokes and subsequent fatal events, and certain patient populations (e.g. women) have a higher risk of bleeding from antiplatelet therapy. Recognizing that the optimal duration of such therapy remains unknown, the advisory panel recommended that the instructions for use of both stents include a reference to the current ACC/AHA/SCAI [4] guidelines for DES implantation during percutaneous coronary interventions, which state that DAPT should be continued for 12 months in patients who are not at high risk for bleeding. The panel was in agreement that the data regarding use in patients outside of the approved indications for use are limited and that the results from use of DES in these patients and lesion subsets should not necessarily be expected to be the same as the results from the clinical trials conducted to support marketing approval. Also, the magnitude of those risks, compared to that posed by alternative treatments for such high-risk patients, remains unknown. The panel also agreed that it is uncertain whether the increased rate of stent thrombosis seen more than 1 year
Vol. 4, No. 2 2007
after implantation, even with on-label use, will ultimately translate into increased rates of MI or death. It is unclear whether cases of late stent thrombosis will continue to accrue with longer term follow-up [5], although data from long-term registries show no attenuation of late stent thrombosis out to and beyond 3 years after implantation. Not unexpectedly, compared to use in patients with simple lesions, the risk of thrombosis increases when DES are used in complex lesions and in patients with coexisting conditions, for example, patients with diabetes; acute MI or multiple vessel disease; or lesions involving arterial bifurcations, the left main coronary artery, and long arterial segments. Currently, DES do not carry indications for these higher risk patient and lesion subsets and are therefore referred to as off-label populations. Expert consensus suggests that late stent thrombosis with DES is likely to be multifactorial, including the specific DES platform characteristics (e.g. all DES may not be alike), the adequacy of stent technique at implantation, unique patient metabolic and rheologic characteristics, and the adequacy of adjunctive DAPT. Of all these, early interruption of DAPT is the most unequivocal risk for stent thrombosis. By contrast, the optimal long-term duration of DAPT is unknown. FDA agreed with the panel’s view that when DES are used under their approved indications [6], the risk of thrombosis does not outweigh their advantages over bare-metal stents in reducing the rate of repeat revascularization. Furthermore, FDA concurs with the panel’s recommendation that larger and longer studies be conducted, focusing on important safety endpoints (MI and death) and on the appropriate duration of DAPT. FDA also believes that randomized, controlled trials are needed to determine the best treatment strategies for lesions in patients with common, yet complex, conditions such as multivessel coronary disease and acute MI.
Critical path: feasible immediate steps FDA’s mission is to protect the public health by ensuring the safety, efficacy of the products under its jurisdiction. FDA is also responsible for advancing the public health by helping to speed innovations that make medicines more effective and affordable and safer. As part of the goal of speeding innovation, FDA’s CPI [1] seeks to identify and address those scientific and technical obstacles to the optimum development of safe and therapeutically important medical products. Under the CPI, FDA is pursuing collaborations with multiple parties and pooling expertise and resources to find innovative ways of reducing the time it takes to bring new and therapeutically important medical products to the market, including identifying safety concerns of new medical products throughout their entire lifecycle. DESs are no exception to this paradigm. First steps from a CPI perspective focuses on two issues: (1) the unique public health issues of this particular cardiac
Drug Discovery Today: Technologies | Critical path
safety question and (2) dimensions of the regulatory landscape whose evolution could improve both current and future evaluation of DES safety. The public health issue relates to the more than 6 million human subjects who already have permanently implanted durable polymer DES stents, with no evidence to define how long they should stay on DAPT. This issue is compounded by the insertion of DES in more than 750,000 additional patients per annum, the emergence of newer DES platforms whose long-term safety is less completely defined than current products, and the emergence of new drugs that could be used in DAPT regimens.
Cardiac safety research consortium (CSRC) To help answer some of the aforementioned questions regarding the risks of DES use and the appropriate duration of antiplatelet therapy, FDA and Duke University Medical System (Duke University) have agreed to collaborate with stakeholders under the framework of a previously established public-private partnership called the Cardiac Safety Research Consortium (http://www.cardiac-safety.org). Under the auspices of the CPI, FDA and Duke University publicly launched the CSRC in September 2006 (http://www.fda.gov/bbs/ topics/NEWS/2006/NEW01467.html). The CSRC is focused on identifying scientific gaps in cardiac safety and implementing projects that will bridge these gaps. The CRSC, under the memorandum of understanding (http://www.fda.gov/oc/ mous/academic/225-06-8404.html) governing these activities, decided to form a new program, the DES Thrombosis Critical Path Partnership, with separate working groups and partners, with the specific purpose of identifying the key elements of studies (data-collection/analysis and/or clinical studies) that may be launched under the collaborative framework of the CSRC and specifically for the DES Thrombosis Critical Path Partnership. Such elements may include the examination of appropriate retrospective data, patient characteristics, for example, concomitant medications and comorbidities, and significant demographic features, for example, sex, age, ethnicity. Under the CSRC, the DES Thrombosis Critical Path Partnership was developed to consider novel clinical trial designs for premarket and postmarket determination of cardiac safety in the setting of obligate drug–device safety interactions, such as has been identified with DAPT and DES. To define how a clinical trial might be conducted, in which concomitant use of a drug and device (or a drug and a combination product) could be evaluated and the data be used to support labeling changes, a hypothetical scenario was created. In this scenario, a clinical trial would be conducted to evaluate the optimal duration of DAPT in an allcomers population of patients receiving DES. Certain logistical and technical issues were identified as needing to be addressed for such a trial to be successful. Also identified were additional areas of development to further expand our www.drugdiscoverytoday.com
45
Drug Discovery Today: Technologies | Critical path
working knowledge of stent thrombosis and its etiologies. Working groups are being developed to address each of these issues: (1) data warehousing, (2) the development of a minimum clinical data set that would be needed to support the study hypotheses, (3) nested statistical analysis strategies, (4) optimal preclinical animal models to aid in the prediction of stent thrombosis risk and/or to identify promising technologies that could reduce the risk of stent thrombosis, and (5) a stent retrieval initiative to gain critical pathology data on autopsy from stent thrombosis cases. Thus, the DES Thrombosis Critical Path Partnership is focused on a series of specific points: Encourage research that facilitates an understanding of the molecular and pathophysiological interaction of DES with the coronary arterial wall. Identify biomarkers that predict patients at increased risk of developing stent (and late stent) thrombosis; understand the interaction between antiplatelet therapies and development of thrombus. Identify better animal models to adequately assess DES safety in humans Encourage large, randomized clinical trials to establish the optimal dose and duration of antiplatelet therapies across a range of at-risk patient subsets. Encourage specimen retrieval via autopsy of patients who have received DES, and continue discussion of how best to implement this approach (i.e. universal informed consent). Duke University, in collaboration with FDA and others, will evaluate different modalities and research tools to enhance the accrual and assessment of future data, including core minimum data sets, data warehouse structure(s) and statistical analysis applications, to promote greater insight into the clinical link between DES safety and the obligatory use of drug therapies such as DAPT (in use or under development) with aspirin plus clopidogrel and other antiplatelet therapies, and how the risks/benefits of DES and DAPT may change over the course of time. It is hoped that the development of such tools will also facilitate the evaluation of existing data and the application of future data accrued to
46
www.drugdiscoverytoday.com
Vol. 4, No. 2 2007
provide insight into these links in an ongoing fashion as new DES and DAPT emerge.
Final remarks Breakthrough technologies are defined by high impact on previously unmet medical needs, including those involving offlabel uses. In an enormous market such as that represented by the patient population having coronary artery disease, the combination of high usage rates in large numbers of previously unstudied patients may also result in unexpected safety issues. This is likely the case with late stent thrombosis and DES. Uniquely, complete evaluation of this safety issue crosses over drug and device evaluation, not in the form of a combination product, but as an obligatory drug–device interaction. In addition to this crossover, the very rare but catastrophic nature of stent thrombosis will require unique insights to provide assurance of safety without paralyzing the pace and ability to bring more innovative DES platforms forward. Collaboration across medical device manufacturers, academic researchers, professional societies and regulatory authorities catalyzed through the CPI on DES thrombosis holds unique potential for high impact on this challenge. Rigorous independent studies will help the DES community understand more about this issue. Only through continued evidence-based research will patients and doctors be assured of the safest, most effective treatments possible.
Acknowledgement The authors sincerely thank Nancy Derr, of the FDA, for her invaluable contributions in the development of this article.
References 1
2 3 4 5 6
FDA. Innovation or Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products, March 2004. http://www.fda.gov/oc/initiatives/ criticalpath/whitepaper.html http://www.fda.gov/cdrh/safety/cypher3.html Muni, N.I. and Gross, T.P. (2004) Problems with drug-eluting coronary stents – the FDA perspective. N. Engl. J. Med. 351, 1593–1595 http://www.acc.org/qualityandscience/clinical/guidelines/percutaneous/ update/index.pdf Krucoff, M.W. et al. (2007) Drug-eluting stents ‘deliver heartburn’: how do we spell relief going forward? Circulation 115, 2990–2994 Farb, A. and Boam, A.B. (2007) Stent thrombosis redux – the FDA perspective. N. Engl. J. Med. 356, 984–987
Vol. 4, No. 2 2007
Editors-in-Chief Kelvin Lam – Harvard Stem Cell Institute, Harvard University, USA Henk Timmerman – Vrije Universiteit, The Netherlands DRUG DISCOVERY
TODAY
TECHNOLOGIES
Critical path
Drug eluting stents and the critical path initiative: Evolving paradigms for safety evaluation Wendy R. Sanhai1,*, Norman Stockbridge2, Robert P. Fiorentino3, Takahiro Uchida3, Kathleen Uhl4, Mitch W. Krucoff5 1
Office of the Commissioner, Food and Drug Administration (FDA), Rockville, MD, USA Division of Cardiovascular and Renal Products, Center for Drug Evaluation and Research, FDA, Rockville, MD, USA 3 Division of Cardiovascular Devices, Center for Devices and Radiological Health, FDA, Rockville, MD, USA 4 FDA, Rockville, MD, USA 5 Duke University Medical Center, Cardiovascular Devices Unit, Duke Clinical Research Institute, Durham, NC 27710, USA 2
Recent discussions between FDA and other stakeholders have focused on the benefits and risks associated with drug eluting stents (DES). A particular topic of
Section Editor: Janet Woodcock – Food and Drug Administration, Rockville, MD, USA
focus is DES thrombosis, a rare, but serious, clinical event that may occur months to years after the initial implantation. FDA continues vigilant postmarket surveillance of DES currently on the market and is working with stent manufactures to ensure that new DES platforms in the development pipeline are safe and effective. FDA is also taking steps, under its Critical Path Initiative (CPI) [FDA. Innovation or Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products, March 2004. http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html], to help address current and future DES safety issues. This article describes some of these activities.
Introduction Coronary stents are permanently implanted devices that are placed percutaneously in one or more coronary arteries to *Corresponding author: : W.R. Sanhai ([email protected]), M.W. Krucoff ([email protected]) 1740-6749/$ ß 2007 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.ddtec.2007.10.004
restore and maintain patency. A drug eluting stent (DES) is a combination product, in which a device (coronary stent) incorporates a pharmacologically active agent (drug) that is delivered at the site of stent deployment to reduce neointimal hyperplasia that can cause arterial re-narrowing (restenosis) after percutaneous coronary intervention (PCI). A key component of DES platforms is the polymer or equivalent carrier that can be loaded with drug and is bound to the stent. Properties of this polymer carrier determine how much drug is released and over what period of time, for example, determines dose and kinetics of drug delivery with the intent of preventing smooth muscle cell proliferation and extracelluar matrix synthesis resulting in restenosis. Local cellular reactions to the polymer, however, may occur. DES delivery is accomplished via expanding an inflatable balloon, on which the stent has been mounted or crimped. Balloon inflation deploys the stent against the inner arterial wall and inevitably traumatizes the artery in the locale of deployment. After a DES is implanted, it slowly releases the drug from its stent platform over a period of weeks or months. The major benefit of a DES is that the medication provided 43
Drug Discovery Today: Technologies | Critical path
helps to prevent restenosis, the formation of neointimal, or scar, tissue that reblocks the artery. Additional systemic antiplatelet medications are typically used in patients receiving DES to minimize risk of platelet thrombus formation while the vascular tissue recovers from localized trauma and as endothelium grows over the DES platform. Antiplatelet therapy involves indefinite, daily aspirin therapy combined with a finite course of clopidogrel (or less commonly ticlopidine), which in combination is referred to as dual antiplatelet therapy (DAPT). FDA and stakeholders are continuing to explore the benefits and risks of DES use. Although the efficacy of these combination products is well accepted, there is growing concern that the risk of stent thrombosis, with catastrophic clinical results, such as myocardial infarction (MI) or death, could persist over the lifetime of patients implanted with DES. Particular attention has been given to late stent thrombosis, defined as thrombosis occurring after 1 year postimplantation.
Key technologies Since their introduction, DESs have been implanted in millions of people worldwide with coronary artery disease. These tiny metal mesh tubes, coated with polymer loaded with drugs that inhibit cell reproduction, are designed to re-establish patency in arteries that may have been partially or completely blocked by arteriosclerotic plaque. In current DES, the drug is incorporated into and released from a polymeric coating of sufficient capacity to accommodate the selected dose and to modulate its delivery at the intended site of action and for the intended duration. The chemical, physical and mechanical attributes of the polymer coating system are important for stent deployment, biocompatibility and stability. To date, FDA has approved two DES for commercial distribution – the Cypher-sirolimus DES (Cordis, approved April 24, 2003) and the Taxus-paclitaxel DES (Boston Scientific, approved March 3, 2004) – and believes that, if used as labeled, these medical devices are both safe and effective. However, noting some reports of subacute stent thrombosis (24 h to 30 days post-implant) in one particular DES and recognizing this as a serious adverse event that is sometimes associated with acute MI or sudden death, FDA alerted physicians to these reports in July and October 2003 [2]. FDA concluded there was no evidence to suggest that use of this DES, when implanted in accordance with the approved indications, was associated with an excess of subacute thromboses as compared with bare-metal stents [3]. Of note, subacute stent thrombosis had been previously observed with bare metal stents, prompting treatment with DAPT postimplantation. DAPT is also required for DES clinical trials and is recommended in all relevant medical practice guidelines. 44
www.drugdiscoverytoday.com
Vol. 4, No. 2 2007
FDA has been monitoring the use of coronary DES and associated patient outcomes since they came on the U.S. market in 2003 and 2004 and will continue to do so. Most recently, FDA attention has been drawn to studies suggesting that DES may pose a small but significant risk of late stent thrombosis (after 1-year post-implantation) not observed during premarket studies. The agency is keenly interested in this issue since such events are often associated with serious adverse outcomes for patients. To help address some of these important issues, FDA convened a meeting of its Circulatory System Devices Advisory Panel on December 7 and 8, 2006, to examine the safety of these devices. Some of the major objectives of this Advisory Panel were to obtain consensus from experts and stakeholders in the field to inform FDA’s activities regarding the incidence and timing of stent thrombosis as well as the appropriate duration of DAPT use in patients who receive DES. This panel assisted the agency in the review and analysis of the available scientific data and provided recommendations for appropriate actions to address this issue. Recommendations included possible modification of the device labeling and the need for additional clinical studies. Perspectives following the panel meeting were as follows: Based on data presented from nonrandomized studies, the panel concluded that a more prolonged course of clopidogrel than that recommended in the stent labels (currently 3 months for recipients of the Cypher stent and 6 months for recipients of the Taxus stent) is likely to be beneficial. Nevertheless, stent thrombosis may occur despite continued DAPT. Antiplatelet therapy carries the small risk of hemorrhage, including strokes and subsequent fatal events, and certain patient populations (e.g. women) have a higher risk of bleeding from antiplatelet therapy. Recognizing that the optimal duration of such therapy remains unknown, the advisory panel recommended that the instructions for use of both stents include a reference to the current ACC/AHA/SCAI [4] guidelines for DES implantation during percutaneous coronary interventions, which state that DAPT should be continued for 12 months in patients who are not at high risk for bleeding. The panel was in agreement that the data regarding use in patients outside of the approved indications for use are limited and that the results from use of DES in these patients and lesion subsets should not necessarily be expected to be the same as the results from the clinical trials conducted to support marketing approval. Also, the magnitude of those risks, compared to that posed by alternative treatments for such high-risk patients, remains unknown. The panel also agreed that it is uncertain whether the increased rate of stent thrombosis seen more than 1 year
Vol. 4, No. 2 2007
after implantation, even with on-label use, will ultimately translate into increased rates of MI or death. It is unclear whether cases of late stent thrombosis will continue to accrue with longer term follow-up [5], although data from long-term registries show no attenuation of late stent thrombosis out to and beyond 3 years after implantation. Not unexpectedly, compared to use in patients with simple lesions, the risk of thrombosis increases when DES are used in complex lesions and in patients with coexisting conditions, for example, patients with diabetes; acute MI or multiple vessel disease; or lesions involving arterial bifurcations, the left main coronary artery, and long arterial segments. Currently, DES do not carry indications for these higher risk patient and lesion subsets and are therefore referred to as off-label populations. Expert consensus suggests that late stent thrombosis with DES is likely to be multifactorial, including the specific DES platform characteristics (e.g. all DES may not be alike), the adequacy of stent technique at implantation, unique patient metabolic and rheologic characteristics, and the adequacy of adjunctive DAPT. Of all these, early interruption of DAPT is the most unequivocal risk for stent thrombosis. By contrast, the optimal long-term duration of DAPT is unknown. FDA agreed with the panel’s view that when DES are used under their approved indications [6], the risk of thrombosis does not outweigh their advantages over bare-metal stents in reducing the rate of repeat revascularization. Furthermore, FDA concurs with the panel’s recommendation that larger and longer studies be conducted, focusing on important safety endpoints (MI and death) and on the appropriate duration of DAPT. FDA also believes that randomized, controlled trials are needed to determine the best treatment strategies for lesions in patients with common, yet complex, conditions such as multivessel coronary disease and acute MI.
Critical path: feasible immediate steps FDA’s mission is to protect the public health by ensuring the safety, efficacy of the products under its jurisdiction. FDA is also responsible for advancing the public health by helping to speed innovations that make medicines more effective and affordable and safer. As part of the goal of speeding innovation, FDA’s CPI [1] seeks to identify and address those scientific and technical obstacles to the optimum development of safe and therapeutically important medical products. Under the CPI, FDA is pursuing collaborations with multiple parties and pooling expertise and resources to find innovative ways of reducing the time it takes to bring new and therapeutically important medical products to the market, including identifying safety concerns of new medical products throughout their entire lifecycle. DESs are no exception to this paradigm. First steps from a CPI perspective focuses on two issues: (1) the unique public health issues of this particular cardiac
Drug Discovery Today: Technologies | Critical path
safety question and (2) dimensions of the regulatory landscape whose evolution could improve both current and future evaluation of DES safety. The public health issue relates to the more than 6 million human subjects who already have permanently implanted durable polymer DES stents, with no evidence to define how long they should stay on DAPT. This issue is compounded by the insertion of DES in more than 750,000 additional patients per annum, the emergence of newer DES platforms whose long-term safety is less completely defined than current products, and the emergence of new drugs that could be used in DAPT regimens.
Cardiac safety research consortium (CSRC) To help answer some of the aforementioned questions regarding the risks of DES use and the appropriate duration of antiplatelet therapy, FDA and Duke University Medical System (Duke University) have agreed to collaborate with stakeholders under the framework of a previously established public-private partnership called the Cardiac Safety Research Consortium (http://www.cardiac-safety.org). Under the auspices of the CPI, FDA and Duke University publicly launched the CSRC in September 2006 (http://www.fda.gov/bbs/ topics/NEWS/2006/NEW01467.html). The CSRC is focused on identifying scientific gaps in cardiac safety and implementing projects that will bridge these gaps. The CRSC, under the memorandum of understanding (http://www.fda.gov/oc/ mous/academic/225-06-8404.html) governing these activities, decided to form a new program, the DES Thrombosis Critical Path Partnership, with separate working groups and partners, with the specific purpose of identifying the key elements of studies (data-collection/analysis and/or clinical studies) that may be launched under the collaborative framework of the CSRC and specifically for the DES Thrombosis Critical Path Partnership. Such elements may include the examination of appropriate retrospective data, patient characteristics, for example, concomitant medications and comorbidities, and significant demographic features, for example, sex, age, ethnicity. Under the CSRC, the DES Thrombosis Critical Path Partnership was developed to consider novel clinical trial designs for premarket and postmarket determination of cardiac safety in the setting of obligate drug–device safety interactions, such as has been identified with DAPT and DES. To define how a clinical trial might be conducted, in which concomitant use of a drug and device (or a drug and a combination product) could be evaluated and the data be used to support labeling changes, a hypothetical scenario was created. In this scenario, a clinical trial would be conducted to evaluate the optimal duration of DAPT in an allcomers population of patients receiving DES. Certain logistical and technical issues were identified as needing to be addressed for such a trial to be successful. Also identified were additional areas of development to further expand our www.drugdiscoverytoday.com
45
Drug Discovery Today: Technologies | Critical path
working knowledge of stent thrombosis and its etiologies. Working groups are being developed to address each of these issues: (1) data warehousing, (2) the development of a minimum clinical data set that would be needed to support the study hypotheses, (3) nested statistical analysis strategies, (4) optimal preclinical animal models to aid in the prediction of stent thrombosis risk and/or to identify promising technologies that could reduce the risk of stent thrombosis, and (5) a stent retrieval initiative to gain critical pathology data on autopsy from stent thrombosis cases. Thus, the DES Thrombosis Critical Path Partnership is focused on a series of specific points: Encourage research that facilitates an understanding of the molecular and pathophysiological interaction of DES with the coronary arterial wall. Identify biomarkers that predict patients at increased risk of developing stent (and late stent) thrombosis; understand the interaction between antiplatelet therapies and development of thrombus. Identify better animal models to adequately assess DES safety in humans Encourage large, randomized clinical trials to establish the optimal dose and duration of antiplatelet therapies across a range of at-risk patient subsets. Encourage specimen retrieval via autopsy of patients who have received DES, and continue discussion of how best to implement this approach (i.e. universal informed consent). Duke University, in collaboration with FDA and others, will evaluate different modalities and research tools to enhance the accrual and assessment of future data, including core minimum data sets, data warehouse structure(s) and statistical analysis applications, to promote greater insight into the clinical link between DES safety and the obligatory use of drug therapies such as DAPT (in use or under development) with aspirin plus clopidogrel and other antiplatelet therapies, and how the risks/benefits of DES and DAPT may change over the course of time. It is hoped that the development of such tools will also facilitate the evaluation of existing data and the application of future data accrued to
46
www.drugdiscoverytoday.com
Vol. 4, No. 2 2007
provide insight into these links in an ongoing fashion as new DES and DAPT emerge.
Final remarks Breakthrough technologies are defined by high impact on previously unmet medical needs, including those involving offlabel uses. In an enormous market such as that represented by the patient population having coronary artery disease, the combination of high usage rates in large numbers of previously unstudied patients may also result in unexpected safety issues. This is likely the case with late stent thrombosis and DES. Uniquely, complete evaluation of this safety issue crosses over drug and device evaluation, not in the form of a combination product, but as an obligatory drug–device interaction. In addition to this crossover, the very rare but catastrophic nature of stent thrombosis will require unique insights to provide assurance of safety without paralyzing the pace and ability to bring more innovative DES platforms forward. Collaboration across medical device manufacturers, academic researchers, professional societies and regulatory authorities catalyzed through the CPI on DES thrombosis holds unique potential for high impact on this challenge. Rigorous independent studies will help the DES community understand more about this issue. Only through continued evidence-based research will patients and doctors be assured of the safest, most effective treatments possible.
Acknowledgement The authors sincerely thank Nancy Derr, of the FDA, for her invaluable contributions in the development of this article.
References 1
2 3 4 5 6
FDA. Innovation or Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products, March 2004. http://www.fda.gov/oc/initiatives/ criticalpath/whitepaper.html http://www.fda.gov/cdrh/safety/cypher3.html Muni, N.I. and Gross, T.P. (2004) Problems with drug-eluting coronary stents – the FDA perspective. N. Engl. J. Med. 351, 1593–1595 http://www.acc.org/qualityandscience/clinical/guidelines/percutaneous/ update/index.pdf Krucoff, M.W. et al. (2007) Drug-eluting stents ‘deliver heartburn’: how do we spell relief going forward? Circulation 115, 2990–2994 Farb, A. and Boam, A.B. (2007) Stent thrombosis redux – the FDA perspective. N. Engl. J. Med. 356, 984–987