Enhancing Post-Marketing Surveillance: Continuing Challenges Dustin D. French, PhD,1 Curtis E. Margo, MD, MPH,2 Robert R. Campbell JD, MPH, PhD,3 1
Center for Healthcare Studies, Department of Ophthalmology, Northwestern University
Feinberg School of Medicine, and Department of Veterans Affairs Health Services Research and Development, Chicago, Illinois 2
Department of Ophthalmology Morsani College of Medicine, University of South
Florida, Tampa, Florida 3
VA Center of Innovation on Disability Rehabilitation Research (CINDRR), VISN-8
Patient Safety Center of Inquiry, Tampa, Florida, Nova Southeastern College of Law, Fort Lauderdale, Florida Financial Disclosures: Funding/Support: Dr. French is supported on an unrestricted grant from Research to Prevent Blindness, NY, NY and Department of Health and Human Services National Institutes of Health, NATIONAL EYE INSTITUTE Grant Number: 1R21EY024050-01A1. Drs. Margo and Campbell have no financial disclosures to report. Correspondence: Dustin D. French, PhD 645 N. Michigan Ave, Suite 440, Chicago IL 60611 or 633 N. St. Clair St., 20th Floor, Chicago IL 60611 [email protected] [email protected] [email protected]
Word count: 1069; References 12. KEY WORDS: Drug Safety; Post-marketing Surveillance; Food and Drug Administration; European Medicines Agency; Erectile Dysfunction; Phosphodiesterase (PDE)-5 inhibitors; Vision Loss;
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/bcp.12658 This article is protected by copyright. All rights reserved.
In this issue, Zeitoun and colleagues (1) examined whether any relationship existed between the speed of European Medicines Agency (EMA) regulatory review of 161 medicines between 2001 and 2010 and reported post-market safety events; they found no relevant correlation. Neither rapid EMA regulatory review nor approval near the deadline was associated with greater reports of adverse events. The findings are reassuring, given the pressure regulatory agencies face to achieve timely reviews and to ensure public safety. There is evidence, however, that the rush to approve new medicines may compromise safety, at least in the United States. Since the approval process at the Food and Drug Administration (FDA) was accelerated through a legislative cost-shifting strategy known as the Prescription Drug User Fee Act in 1992, both post-marketing black-box warning and market withdrawals have significantly increased.(2) But the tensions affecting one regulatory system may not be applicable to another. The process of pre-market approval should also be viewed as just one facet of pharmaceutical safety. While the findings of Zeitoun et al. (1) are encouraging, neither regulatory agencies nor the public should become complacent. Belated discovery of serious adverse drug events is not always the result of poorly conducted clinical trials, nefarious drug companies, or weak regulatory oversight; some drug-related complications reflect the complexities of human biology. The most meticulous regulatory review will never guarantee the detection of all adverse drug effects. Maintaining a robust system of post-marketing surveillance must complement a thorough drug approval process. However, these processes too are often thwarted by limitations of health record data and corresponding decision support tools (e.g., dashboards, data cubes, etc.), and the practice of off-label prescribing. Phosphodiesterase (PDE)-5 inhibitors for erectile dysfunction (ED) and non-arteritic ischemic optic neuropathy (NAION) provides a prime example of the elusive nature of drug safety. From 2002 through 2005, reports linking the use of phosphodiesterase PDE-5 inhibitors for ED and non-arteritic ischemic optic neuropathy (NAION) appeared in the literature.(3) Establishing the causal association between serious complications and drug
This article is protected by copyright. All rights reserved.
use can be an arduous task, even when the adverse event is as clinically evident as vision loss. This complication had not been reported in pre-marketing clinical trials. Patients in the post-marketing phase described vision loss within 30 minutes to 36 hours after drug use. A biologically plausible explanation for ischemic injury to the optic nerve was evident from the start: PDE-5 inhibitors are capable of transiently lowering blood pressure. This transient dip in pressure could reduce vascular perfusion of the optic nerve head enough to result in localized infarction. By the fall of 2005, Public Citizen, a non-profit consumer organization, petitioned the FDA to add a black-box warning on all PDE-5 inhibitors, having gathered sufficient post-marketing evidence to consider the risk of vision loss a matter of public safety.(4) Skeptics noted that the men who use PDE-5 inhibitors for ED are also those who are at the highest risk for NAION – that is, men who have diabetes and atherosclerotic vascular disease. In 2007, a large retrospective cohort study involving 4,157,357 male veterans found no increased risk of NAION in men prescribed PDE-5 inhibitors (odds ratio 1.02 [95% confidence interval 0.92-1.12]).(5) Similar findings using administrative data have continued to accumulate, despite anecdotal reports of the close temporal relationships between drug exposure and vision loss.(6,7) One pharmaceutical company conducted its own prospective study and found a twofold increased risk of NAION within five half-lives of PDE-5 inhibitor use, a hazard that translates to three additional cases of NAION per 100,000 men 50 years and older each year.(8) More than 13 years have passed since the first cases of PDE-5 inhibitor exposure and NAION were reported and the real risk of drug-related vision loss remains unsettled. Rare but serious adverse drug-related events are a challenge to detect and even more daunting to establish as causal. An effective post-marketing surveillance system with clinically integrated health records and data systems is critical for proactively finding “rare events” and assessing risks. The process of post-marketing surveillance in the United States suffers because reporting of adverse events operates on a voluntary basis.(9) Patients may This article is protected by copyright. All rights reserved.
traverse a myriad of different doctors and healthcare systems in a lifetime.(10) Without clinical integration of electronic health records across institutions and between providers (e.g., lifetime electronic health record), regulatory agencies, doctors and researchers cannot be expected to identify rare but potentially serious adverse events in a meaningful time frame. Additionally, fully integrated healthcare records would require supporting software tools (data extraction tools, dashboards, data cubes, etc.) that would facilitate effective data management and analysis for post-marketing surveillance. Why is post-marketing surveillance so important for public safety? One reason is that once a new medication is approved its use in the medical community may vary considerably from the context in which it was tested for safety. The FDA approves drugs for indicated use but does not control how physicians prescribe medications. This allows physicians wide discretion to prescribe “off-label” or outside of FDA indicated uses. Recent FDA guidance on physician off-label practices states that “If physicians use a product for an indication not in the approved labeling, they have the responsibility to be well-informed about the product, to base its use on firm scientific rationale and on sound medical evidence, and to maintain records of the product's use and effects.”(11) It is estimated that 20% of all prescriptions in the United States are currently prescribed outside of FDA indications for use, or “off-label.” There are no FDA requirements for a physician to inform patients that they are prescribing a medication “off-label.” (12) This practice has been a persistent obstacle to effective postmarketing surveillance of drugs because it can alter drug dosage, mode of administration, and duration of use. It also means that drugs are being used in a population of patients that likely differ from those which safety was ascertained.(12) Drug safety requires a multifaceted approach from pre-market approval to postmarketing surveillance. Rare but serious adverse events can be difficult to causally link with drug exposure even when a plausible mechanism of injury exists. Optimal post-marketing surveillance cannot be based on voluntary reporting systems alone. The off-label use of drugs further confounds the problem of drug safety by exposing populations of patients that This article is protected by copyright. All rights reserved.
may fundamentally differ from those in pre-market assessments of safety. Having an integrated large-scale medical record with a corresponding data retrieval system and decision support analytics for post-marketing surveillance would be an important first step in confronting these challenges. References 1. Zeitoun J-D, Lefèvre JH, Downing NS, Bergeron H, Ross JS. Regulatory review time and post-market safety events for novel medicines approved by the EMA between 2001 and 2010: a cross-sectional study. Br J Clinic Pharm (in press). 2. Frank C, Himmelstein DU, Woolhandler S, Bor DH, Wolfe SM, Heymann O, Zallman L, Lasser KE. Era of faster FDA drug approval has also seen increased black-box warning and market withdrawals. Health Affairs 2015;33:1353-9. 3. Pomeranz HD, Bhavsar AR. Nonarteritic ischemic optic neuropathy developing soon after use of sildenafil (viagra): a report of seven new cases. J Neuroophthalmol. 2005 Mar;25:9-13. 4. Barbehenn E. Lurie P, Wolfe SM, Pomeranz HD. Petition to require a black box warning for erectile dysfunction drugs sildenafil (Viagra), tadalafil (Cialis) and vardenafil (Levitra). http://www.citizen.org/ (accessed March 24, 2015). 5. Margo CE, French DD. Ischemic optic neuropathy in male veterans prescribed phosphodiesterase-5 inhibitors. Am J Ophthlamol 2007;143:538-9. 6. Nathoo NA, Etminan M, Mikelberg FS. Association between phosphodiesterase-5 inhibitors and nonarteritic anterior ischemic optic neuropathy. J Neuro-Ophthalmol 2015;35:12-5 7. French DD, Margo CE. Post-marketing surveillance of ischaemic optic neuropathy in male veterans co-prescribed phosphodiesterase-5 inhibitors with organic nitrates or alpha-blockers. Drug Saf. 2008;31(3):241-7. 8. Campbell UB, Walker AM, Gaffney M, Petronis KR, Creanga D, Quinn S, Klein BE, Laties AM, Lewis M, Sharlip ID, Kolitsopoulos F, Klee BJ, Mo J, Reynolds RF. Acute nonarteritic anterior ischemic opticn neuropathy and exposure to phosphodiesterase type 5 inhibitors. J Sex Med 2015;12:139-51. 9. Campbell RR, Spehar AM, French DD. Proactive Postmarketing Surveillance: Overview and Lessons Learned from Medication Safety Research in the Veterans Health Administration. In: Henriksen K, Battles JB, Keyes MA, Grady ML, editors. Advances in Patient Safety: New Directions and Alternative Approaches (Vol. 1: Assessment). Rockville (MD): Agency for Healthcare Research and Quality; 2008 Aug. Available online: http://www.ahrq.gov/professionals/quality-patient-safety/patient-safetyresources/resources/advances-in-patient-safety-2/vol1/Advances-Campbell-R_106.pdf (accessed April 1, 2015).
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10. French DD. Impact of Health Information Exchange on VA Patient Costs. Academy Health National Meeting, June 2014. San Diego, CA. Available at: http://www.academyhealth.org/files/2014/monday/french.pdf (accessed April 1, 2015). 11. FDA Guidance, 2014: "Off-Label" and Investigational Use Of Marketed Drugs, Biologics, and Medical Devices - Information Sheet-Guidance for Institutional Review Boards and Clinical Investigators. Available online: http://www.fda.gov/RegulatoryInformation/Guidances/ucm126486.htm (accessed March 30, 2015). 12. Rodwin, M. Journal of Law Medicine and Ethics: Fall 2013: 654-664. Rooting out institutional corruption to manage inappropriate off-label drug use.
This article is protected by copyright. All rights reserved.
Center for Healthcare Studies, Department of Ophthalmology, Northwestern University
Feinberg School of Medicine, and Department of Veterans Affairs Health Services Research and Development, Chicago, Illinois 2
Department of Ophthalmology Morsani College of Medicine, University of South
Florida, Tampa, Florida 3
VA Center of Innovation on Disability Rehabilitation Research (CINDRR), VISN-8
Patient Safety Center of Inquiry, Tampa, Florida, Nova Southeastern College of Law, Fort Lauderdale, Florida Financial Disclosures: Funding/Support: Dr. French is supported on an unrestricted grant from Research to Prevent Blindness, NY, NY and Department of Health and Human Services National Institutes of Health, NATIONAL EYE INSTITUTE Grant Number: 1R21EY024050-01A1. Drs. Margo and Campbell have no financial disclosures to report. Correspondence: Dustin D. French, PhD 645 N. Michigan Ave, Suite 440, Chicago IL 60611 or 633 N. St. Clair St., 20th Floor, Chicago IL 60611 [email protected] [email protected] [email protected]
Word count: 1069; References 12. KEY WORDS: Drug Safety; Post-marketing Surveillance; Food and Drug Administration; European Medicines Agency; Erectile Dysfunction; Phosphodiesterase (PDE)-5 inhibitors; Vision Loss;
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/bcp.12658 This article is protected by copyright. All rights reserved.
In this issue, Zeitoun and colleagues (1) examined whether any relationship existed between the speed of European Medicines Agency (EMA) regulatory review of 161 medicines between 2001 and 2010 and reported post-market safety events; they found no relevant correlation. Neither rapid EMA regulatory review nor approval near the deadline was associated with greater reports of adverse events. The findings are reassuring, given the pressure regulatory agencies face to achieve timely reviews and to ensure public safety. There is evidence, however, that the rush to approve new medicines may compromise safety, at least in the United States. Since the approval process at the Food and Drug Administration (FDA) was accelerated through a legislative cost-shifting strategy known as the Prescription Drug User Fee Act in 1992, both post-marketing black-box warning and market withdrawals have significantly increased.(2) But the tensions affecting one regulatory system may not be applicable to another. The process of pre-market approval should also be viewed as just one facet of pharmaceutical safety. While the findings of Zeitoun et al. (1) are encouraging, neither regulatory agencies nor the public should become complacent. Belated discovery of serious adverse drug events is not always the result of poorly conducted clinical trials, nefarious drug companies, or weak regulatory oversight; some drug-related complications reflect the complexities of human biology. The most meticulous regulatory review will never guarantee the detection of all adverse drug effects. Maintaining a robust system of post-marketing surveillance must complement a thorough drug approval process. However, these processes too are often thwarted by limitations of health record data and corresponding decision support tools (e.g., dashboards, data cubes, etc.), and the practice of off-label prescribing. Phosphodiesterase (PDE)-5 inhibitors for erectile dysfunction (ED) and non-arteritic ischemic optic neuropathy (NAION) provides a prime example of the elusive nature of drug safety. From 2002 through 2005, reports linking the use of phosphodiesterase PDE-5 inhibitors for ED and non-arteritic ischemic optic neuropathy (NAION) appeared in the literature.(3) Establishing the causal association between serious complications and drug
This article is protected by copyright. All rights reserved.
use can be an arduous task, even when the adverse event is as clinically evident as vision loss. This complication had not been reported in pre-marketing clinical trials. Patients in the post-marketing phase described vision loss within 30 minutes to 36 hours after drug use. A biologically plausible explanation for ischemic injury to the optic nerve was evident from the start: PDE-5 inhibitors are capable of transiently lowering blood pressure. This transient dip in pressure could reduce vascular perfusion of the optic nerve head enough to result in localized infarction. By the fall of 2005, Public Citizen, a non-profit consumer organization, petitioned the FDA to add a black-box warning on all PDE-5 inhibitors, having gathered sufficient post-marketing evidence to consider the risk of vision loss a matter of public safety.(4) Skeptics noted that the men who use PDE-5 inhibitors for ED are also those who are at the highest risk for NAION – that is, men who have diabetes and atherosclerotic vascular disease. In 2007, a large retrospective cohort study involving 4,157,357 male veterans found no increased risk of NAION in men prescribed PDE-5 inhibitors (odds ratio 1.02 [95% confidence interval 0.92-1.12]).(5) Similar findings using administrative data have continued to accumulate, despite anecdotal reports of the close temporal relationships between drug exposure and vision loss.(6,7) One pharmaceutical company conducted its own prospective study and found a twofold increased risk of NAION within five half-lives of PDE-5 inhibitor use, a hazard that translates to three additional cases of NAION per 100,000 men 50 years and older each year.(8) More than 13 years have passed since the first cases of PDE-5 inhibitor exposure and NAION were reported and the real risk of drug-related vision loss remains unsettled. Rare but serious adverse drug-related events are a challenge to detect and even more daunting to establish as causal. An effective post-marketing surveillance system with clinically integrated health records and data systems is critical for proactively finding “rare events” and assessing risks. The process of post-marketing surveillance in the United States suffers because reporting of adverse events operates on a voluntary basis.(9) Patients may This article is protected by copyright. All rights reserved.
traverse a myriad of different doctors and healthcare systems in a lifetime.(10) Without clinical integration of electronic health records across institutions and between providers (e.g., lifetime electronic health record), regulatory agencies, doctors and researchers cannot be expected to identify rare but potentially serious adverse events in a meaningful time frame. Additionally, fully integrated healthcare records would require supporting software tools (data extraction tools, dashboards, data cubes, etc.) that would facilitate effective data management and analysis for post-marketing surveillance. Why is post-marketing surveillance so important for public safety? One reason is that once a new medication is approved its use in the medical community may vary considerably from the context in which it was tested for safety. The FDA approves drugs for indicated use but does not control how physicians prescribe medications. This allows physicians wide discretion to prescribe “off-label” or outside of FDA indicated uses. Recent FDA guidance on physician off-label practices states that “If physicians use a product for an indication not in the approved labeling, they have the responsibility to be well-informed about the product, to base its use on firm scientific rationale and on sound medical evidence, and to maintain records of the product's use and effects.”(11) It is estimated that 20% of all prescriptions in the United States are currently prescribed outside of FDA indications for use, or “off-label.” There are no FDA requirements for a physician to inform patients that they are prescribing a medication “off-label.” (12) This practice has been a persistent obstacle to effective postmarketing surveillance of drugs because it can alter drug dosage, mode of administration, and duration of use. It also means that drugs are being used in a population of patients that likely differ from those which safety was ascertained.(12) Drug safety requires a multifaceted approach from pre-market approval to postmarketing surveillance. Rare but serious adverse events can be difficult to causally link with drug exposure even when a plausible mechanism of injury exists. Optimal post-marketing surveillance cannot be based on voluntary reporting systems alone. The off-label use of drugs further confounds the problem of drug safety by exposing populations of patients that This article is protected by copyright. All rights reserved.
may fundamentally differ from those in pre-market assessments of safety. Having an integrated large-scale medical record with a corresponding data retrieval system and decision support analytics for post-marketing surveillance would be an important first step in confronting these challenges. References 1. Zeitoun J-D, Lefèvre JH, Downing NS, Bergeron H, Ross JS. Regulatory review time and post-market safety events for novel medicines approved by the EMA between 2001 and 2010: a cross-sectional study. Br J Clinic Pharm (in press). 2. Frank C, Himmelstein DU, Woolhandler S, Bor DH, Wolfe SM, Heymann O, Zallman L, Lasser KE. Era of faster FDA drug approval has also seen increased black-box warning and market withdrawals. Health Affairs 2015;33:1353-9. 3. Pomeranz HD, Bhavsar AR. Nonarteritic ischemic optic neuropathy developing soon after use of sildenafil (viagra): a report of seven new cases. J Neuroophthalmol. 2005 Mar;25:9-13. 4. Barbehenn E. Lurie P, Wolfe SM, Pomeranz HD. Petition to require a black box warning for erectile dysfunction drugs sildenafil (Viagra), tadalafil (Cialis) and vardenafil (Levitra). http://www.citizen.org/ (accessed March 24, 2015). 5. Margo CE, French DD. Ischemic optic neuropathy in male veterans prescribed phosphodiesterase-5 inhibitors. Am J Ophthlamol 2007;143:538-9. 6. Nathoo NA, Etminan M, Mikelberg FS. Association between phosphodiesterase-5 inhibitors and nonarteritic anterior ischemic optic neuropathy. J Neuro-Ophthalmol 2015;35:12-5 7. French DD, Margo CE. Post-marketing surveillance of ischaemic optic neuropathy in male veterans co-prescribed phosphodiesterase-5 inhibitors with organic nitrates or alpha-blockers. Drug Saf. 2008;31(3):241-7. 8. Campbell UB, Walker AM, Gaffney M, Petronis KR, Creanga D, Quinn S, Klein BE, Laties AM, Lewis M, Sharlip ID, Kolitsopoulos F, Klee BJ, Mo J, Reynolds RF. Acute nonarteritic anterior ischemic opticn neuropathy and exposure to phosphodiesterase type 5 inhibitors. J Sex Med 2015;12:139-51. 9. Campbell RR, Spehar AM, French DD. Proactive Postmarketing Surveillance: Overview and Lessons Learned from Medication Safety Research in the Veterans Health Administration. In: Henriksen K, Battles JB, Keyes MA, Grady ML, editors. Advances in Patient Safety: New Directions and Alternative Approaches (Vol. 1: Assessment). Rockville (MD): Agency for Healthcare Research and Quality; 2008 Aug. Available online: http://www.ahrq.gov/professionals/quality-patient-safety/patient-safetyresources/resources/advances-in-patient-safety-2/vol1/Advances-Campbell-R_106.pdf (accessed April 1, 2015).
This article is protected by copyright. All rights reserved.
10. French DD. Impact of Health Information Exchange on VA Patient Costs. Academy Health National Meeting, June 2014. San Diego, CA. Available at: http://www.academyhealth.org/files/2014/monday/french.pdf (accessed April 1, 2015). 11. FDA Guidance, 2014: "Off-Label" and Investigational Use Of Marketed Drugs, Biologics, and Medical Devices - Information Sheet-Guidance for Institutional Review Boards and Clinical Investigators. Available online: http://www.fda.gov/RegulatoryInformation/Guidances/ucm126486.htm (accessed March 30, 2015). 12. Rodwin, M. Journal of Law Medicine and Ethics: Fall 2013: 654-664. Rooting out institutional corruption to manage inappropriate off-label drug use.
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