HHS Public Access Author manuscript Author Manuscript
Monitor (Assoc Clin Pharmacol). Author manuscript; available in PMC 2015 April 13. Published in final edited form as: Monitor (Assoc Clin Pharmacol). 2008 April ; 22(2): 45–48.
Postmarketing Research and Surveillance: Issues and Challenges David B. Resnik, JD, PhD
Author Manuscript
The drug safety system in the United States has come under fire once again, this time due to problems with Food and Drug Administration (FDA)–approved medications that have been on the market for several years. Adverse drug reactions (ADRs) and unanticipated health problems have occurred with the arthritis medications rofecoxib (Vioxx) and celecoxib (Celebrex), the diabetes medication rosiglitazone maleate (Avandia), selective serotonin reuptake inhibitors used to treat adolescents with depression, and dexfenfluramine (Redux) when used in combination with phentermine for weight loss.1 Vioxx, for example, was on the market for more than five years before Merck officials decided to withdraw the drug due to liability and safety concerns. To date, 88,000 people have developed cardiovascular problems while taking Vioxx, and 13,000 lawsuits have been filed against the manufacturer. 2
Author Manuscript
In response to these and other concerns, numerous Congressional hearings have been held on drug safety. One result of these hearings is the FDA Revitalization Act of 2007. This new law includes such measures designed to promote drug safety as mandatory registration of clinical trials of products submitted to the FDA for approval, and restructuring and strengthening of the FDA.3
Author Manuscript
Critics have identified various problems with the U.S. drug safety system, including underfunding of the FDA, financial conflicts of interest on FDA advisory panels and in clinical research, lack of transparency and openness in industry-sponsored research, and an insufficient number of test subjects in premarketing studies.4,5 Most critics also agree that the U.S. postmarketing safety assessment system is woefully inadequate and out of date.6,7 According to one critic, postmarketing safety assessment “is essentially a system developed in the 1950s … the system cannot be used to test hypotheses but simply to generate them.”8 This state of affairs stands in sharp contrast to the scientifically rigorous and innovative premarketing research system used in the U.S., which synthesizes and analyzes data from animal studies and three phases of controlled clinical trials on human subjects.
The U.S. Postmarketing Safety Assessment System The postmarketing safety assessment system consists of basically two methods of data acquisition: postmarketing studies and case reports of adverse drug reactions (ADRs) reported to the FDA under the MedWatch program. The FDA does not require manufacturers to conduct postmarketing studies of their products; it does require manufacturers to report ADRs that come to their attention, but healthcare providers are not required to report ADRs to the FDA or to the drug manufacturers. Manufacturers sometimes
Resnik
Page 2
Author Manuscript
voluntarily agree to conduct postmarketing studies, but less than half of these studies are brought to completion, and the data are often not analyzed.9 Manufacturers may unreasonably delay or block publication of their own or other scientists’ research that is unfavorable to their products, which happened in the Vioxx case mentioned above.10 In addition, postmarketing studies lack the rigor of premarketing studies. They are often not randomized and lack a control group. The focus of many postmarketing studies is on comparing the manufacturer’s drug to competing drugs or testing it for off-label use, rather than on gathering safety data for the drug.
Author Manuscript
The MedWatch system includes a database of unsolicited case reports of ADRs submitted to the FDA by drug manufacturers or healthcare providers (e.g., physicians, dentists, pharmacists, nurses). This system has numerous methodological shortcomings: Reporting is sporadic, potentially biased, and sometimes incomplete, and the case reports often do not conform to required formats. Healthcare providers are the primary source of ADR data for the pharmaceutical companies. Since reporting of ADRs by healthcare providers is voluntary, underreporting is a major concern.11 According to the FDA, only about 1% of serious ADRs are reported.12 There are at least two reasons why health providers under-report ADRs. First, there is no financial incentive: reporting is purely voluntary. It takes time to fill and submit an ADR, and time is money in a busy clinical practice. Second, healthcare providers might have difficulty recognizing ADRs, due to confusion about applying the definition of an ADR to particular cases.
Author Manuscript
The World Health Organization (WHO) defines an ADR as “any response to a drug which is noxious and unintended, and which occurs at doses normally used in humans for prophylaxis, diagnosis, or therapy of disease, or for the modification of physiological function.”13 This definition is vague and can include common complaints and ailments, most of which are “noxious and unintended.” The source of the ailment, whether medically related or due to an ADR, is often difficult to discern. Healthcare providers do not have the time and resources to investigate every medical problem they encounter as a possible ADR. For example, if a 72-year-old male is having a myocardial infarction (MI), an emergency room physician will probably view this as simply a case of an MI, not as a possible ADR. Other common problems like shortness of breath, cancer, dementia, and diabetes probably would not be reported as ADRs.
Author Manuscript
Postmarketing Safety Worldwide Postmarketing studies and case reporting of ADRs have some problems in common. First, there is insufficient international cooperation concerning postmarketing drug safety. The WHO’s drug safety monitoring program covers 86 countries, but each country has its own system for regulating drugs.14 Although all 86 countries have access to the WHO’s drug safety database, they can choose to ignore the data when deciding whether to approve, withdraw, or place additional warnings on a drug.
Monitor (Assoc Clin Pharmacol). Author manuscript; available in PMC 2015 April 13.
Resnik
Page 3
Author Manuscript
Clearly, international autonomy is important for drug safety, as each country must weigh the risks and benefits of certain drugs for their own populations. However, greater communication among the different nations would benefit all. Thalidomide, which was used as a treatment for morning sickness during pregnancy, is a case in point. Thalidomide was approved for this use in more than 50 countries in the 1950s and 1960s. In contrast, the U.S. chose not to approve thalidomide for this use, citing a lack of adequate safety data. Thousands of children outside the U.S. suffered severe birth defects from exposure to thalidomide in utero before it was finally withdrawn from the international market.15 Better communication between these countries and the U.S. might have prevented some of these birth defects.
Author Manuscript
Second, neither postmarketing studies nor case reporting of ADRs are designed to assess the long-term risks of drugs. A long-term study can last five years or more.16 Postmarketing studies usually last only two years at most, and many are not brought to completion. Although case reporting of ADRs related to a drug can last indefinitely, case reporting is not a systematic, controlled investigation of the effects of the drug. Case reports are, at best, anecdotal evidence of drug risks. As one critic notes, “A plurality of anecdotes is not data.”17
The Need for Long-Term Studies
Author Manuscript
Long-term studies of drugs can be a valuable source of data for drug safety assessment, since ADRs sometimes materialize only after a patient has been taking a drug for years. For example, the association between hormone replacement therapy and increased cancer risk was discovered only after women had been taking the medications for many years.18 It is not unusual for chemical toxicity to manifest clinically after 10, 15, or 20 or more years of continuous exposure or even many years after a single exposure.19 For example, the average age of onset for lung cancer for pack-a-day smokers is 60 years old.20 Someone who inhales asbestos particles while working at a construction site many not develop mesothelioma for 20 years or more.21
Author Manuscript
An example of a well-designed, long-term drug study that demonstrates the usefulness of postmarketing drug safety research is the research conducted by the Data Collection on Adverse Events of Anti-HIV Drugs (DAD) Study Group. This was a prospective observational study of HIV patients. Data were collected on the incidence of myocardial infarction (MI) and exposure to various HIV medications, controlling for age, sex, bodymass index, blood pressure, smoking status, blood cholesterol levels, and other factors that affect the risk of MI. The investigators found that the patients who took protease inhibitors for six or more years had four times the risk of an MI, compared to those who did not take these drugs. In contrast, nonnucleoside reverse-transcriptase inhibitors did not increase the risk of MI.22 The effect detected by the DAD study group would not have been noticeable based on case reporting alone, because most clinicians would not have recognized the MI as an ADR. Although long-term studies of drugs can provide important information for regulators, healthcare providers, and patients, there are financial, practical, and ethical issues to be
Monitor (Assoc Clin Pharmacol). Author manuscript; available in PMC 2015 April 13.
Resnik
Page 4
Author Manuscript
considered, especially for interventional controlled clinical trials that last five or more years. Therefore, many long-term drug safety studies are based on an observational research design, such as prospective or retrospective case-control or cohort studies.23 Observational designs have their own problems:
Author Manuscript
•
Identifying potential confounders is difficult, and if they are not controlled for, they can cause study bias and misleading results. Consider a long-term drug safety study with elderly patients; potential confounders for declining health might include increasing age or natural disease progression, and both must be controlled for.24
•
Drug safety studies are often conducted at multiple study centers, so data collection, management, and analysis can be problematic.
•
Maintaining contact with subjects for long-term follow-up is needed to minimize attrition; comprehensive follow-up requires study commitment from both the investigators and the subjects.
•
Long-term observational studies are expensive, due to the large numbers of subjects needed for adequate statistical power (e.g., 5,000 or more); the DAD study, for example, enrolled more than 23,000 subjects.
Author Manuscript
Funding long-term drug safety studies is perhaps the biggest challenge of all. Pharmaceutical companies are not likely to pay for long-term drug studies unless required to do so by regulatory agencies. As noted earlier, pharmaceutical companies often fail to complete postmarketing studies, even when they voluntarily agree to conduct them. Government research funding agencies, such as the National Institutes of Health (NIH), already have tight budgets, and spending is often influenced by various special interest groups representing patients, disease foundations, healthcare providers, researchers, and others. The NIH uses the disease burden concept to guide funding allocation decisions. One way to convince the NIH to fund more long-term studies of drugs is to demonstrate that ADRs impose a high disease burden on society. There is solid evidence of this, since each year ADRs kill an estimated 100,000 people and seriously injure 2 million.25
Author Manuscript
Perhaps the best way to fund long-term drug studies is to establish public-private partnerships. To ensure independence, companies would not design and fund studies of their own drugs. Instead, they would contribute money to a common funding pool, which would also include money from the NIH and other parties with a vested interest, such as Medicare. The results of the studies would be reported to regulatory agencies and published. To maximize the return on this research investment, it would be wise to focus, at first, on common diseases that are likely to involve many years of pharmacotherapy, such as arthritis, diabetes, gastric reflux, asthma, attention deficit disorder, and depression. Rarer diseases could be tackled later.
Acknowledgments This article is based on a previously published article: Resnik D. 2007. Beyond post-marketing studies and MedWatch: long-term studies of drug safety. Drug Design, Development and Therapy 1: 1–5.
Monitor (Assoc Clin Pharmacol). Author manuscript; available in PMC 2015 April 13.
Resnik
Page 5
Author Manuscript
This research was supported by the National Institute of Environmental Health Sciences, National Institutes of Health. It does not represent the opinions of the National Institute of Environmental Health Sciences or the National Institutes of Health. The author is grateful to Pat Chulada for helpful comments.
References
Author Manuscript Author Manuscript Author Manuscript
1. Couzin J. Gaps in the safety net. Science. 2005; 307:196–198. [PubMed: 15653480] 2. Prakash S, Valentine V. Timeline: the rise and fall of Vioxx. 2006Accessed May 21, 2007NPR.org, June 8, 2006. Available at www.npr.org/templates/story/story.php?storyId=5470430 3. Guthrie P. US Senate passes FDA Revitalization Act. Canadian Medical Association Journal. 2007; 177:23. [PubMed: 17606930] 4. Institute of Medicine. The Future of Drug Safety: Promoting and Protecting the Health of the Public. Washington: Institute of Medicine; 2006. Available at www.nap.edu/catalog/11750.html#toc [Accessed October 11, 2006] 5. Angell, M. The Truth about Drug Companies. New York: Random House; 2004. 6. Strom B. How the US drug safety system should be changed. Journal of the American Medical Association. 2006; 295:2072–2075. [PubMed: 16670415] 7. Ray W, Stein C. Reform of drug regulation: beyond an independent drug-safety board. New England Journal of Medicine. 2006; 354:194–201. [PubMed: 16407517] 8. Strom. 2006:2072. 9. Fontanarosa P, Rennie D, DeAngelis C. Postmarketing surveillance–lack of vigilance, lack of trust. Journal of the American Medical Association. 2004; 292:2647–2650. [PubMed: 15572723] 10. Resnik, D. The Price of Truth. New York: Oxford University Press; 2007. 11. Strom. 2006:2072. 12. US Food and Drug Administration. [Accessed November 9, 2007] The clinical impact of adverse event reporting. Available at www.fda.gov/medwatch/articles/medcont/postrep.htm 13. Requirements for adverse reaction reporting. Geneva: WHO; 1975. World Health Organization (WHO). 14. World Health Organization (WHO). [Accessed November 10, 2007] The safety of medicines. Available at www.who.int/mediacentre/factsheets/fs293/en/index.html 15. Knightley, P.; Evans, H.; Potter, E.; Wallace, M. Suffer the Children: The Story of Thalidomide. New York: The Viking Press; 1979. 16. Resnik D. Beyond post-marketing studies and MedWatch: long-term studies of drug safety. Drug Design, Development and Therapy. 2007; 1:1–5. 17. Strom. 2006:2072. 18. Ray, Stein. 2006:195. 19. Cranor, C. Toxic Torts. Cambridge: Cambridge University Press; 2006. 20. Rhode Island Cancer Council. Lung Cancer: The Facts. Accessed November 9, 2007Available at www.ricancercouncil.org/cancer-info/lung-cancer-facts.php 21. National Cancer Institute. [Accessed: November 9, 2007] Asbestos Exposure: Questions and Answers. Available at www.cancer.gov/cancertopics/factsheet/Risk/asbestos 22. Friis-Møller N. the DAD Study Group. Class of antiretroviral drugs and the risk of myocardial infarction. New England Journal of Medicine. 2007; 356:1723–1735. [PubMed: 17460226] 23. Resnik. 2007:3. 24. Hughes M, Williams P. Challenges in using observational studies to evaluate adverse effects of treatment. New England Journal of Medicine. 2007; 356:1705–1707. [PubMed: 17460224] 25. Public Citizen. [Accessed November 9, 2007] Adverse drug reactions. 2007. Available at www.worstpills.org/public/page.cfm?op_id=4
Monitor (Assoc Clin Pharmacol). Author manuscript; available in PMC 2015 April 13.
Resnik
Page 6
Author Manuscript
Biography David B. Resnik, JD, PhD, is a bioethicist and IRB vice-chair at the National Institute of Environmental Health Sciences, National Institutes of Health. He has published six books and 130 articles on ethical, philosophical, and legal issues in science, technology, and medicine, and is an associate editor for the journal Accountability in Research. He can be reached at [email protected].
Author Manuscript Author Manuscript Author Manuscript Monitor (Assoc Clin Pharmacol). Author manuscript; available in PMC 2015 April 13.
Monitor (Assoc Clin Pharmacol). Author manuscript; available in PMC 2015 April 13. Published in final edited form as: Monitor (Assoc Clin Pharmacol). 2008 April ; 22(2): 45–48.
Postmarketing Research and Surveillance: Issues and Challenges David B. Resnik, JD, PhD
Author Manuscript
The drug safety system in the United States has come under fire once again, this time due to problems with Food and Drug Administration (FDA)–approved medications that have been on the market for several years. Adverse drug reactions (ADRs) and unanticipated health problems have occurred with the arthritis medications rofecoxib (Vioxx) and celecoxib (Celebrex), the diabetes medication rosiglitazone maleate (Avandia), selective serotonin reuptake inhibitors used to treat adolescents with depression, and dexfenfluramine (Redux) when used in combination with phentermine for weight loss.1 Vioxx, for example, was on the market for more than five years before Merck officials decided to withdraw the drug due to liability and safety concerns. To date, 88,000 people have developed cardiovascular problems while taking Vioxx, and 13,000 lawsuits have been filed against the manufacturer. 2
Author Manuscript
In response to these and other concerns, numerous Congressional hearings have been held on drug safety. One result of these hearings is the FDA Revitalization Act of 2007. This new law includes such measures designed to promote drug safety as mandatory registration of clinical trials of products submitted to the FDA for approval, and restructuring and strengthening of the FDA.3
Author Manuscript
Critics have identified various problems with the U.S. drug safety system, including underfunding of the FDA, financial conflicts of interest on FDA advisory panels and in clinical research, lack of transparency and openness in industry-sponsored research, and an insufficient number of test subjects in premarketing studies.4,5 Most critics also agree that the U.S. postmarketing safety assessment system is woefully inadequate and out of date.6,7 According to one critic, postmarketing safety assessment “is essentially a system developed in the 1950s … the system cannot be used to test hypotheses but simply to generate them.”8 This state of affairs stands in sharp contrast to the scientifically rigorous and innovative premarketing research system used in the U.S., which synthesizes and analyzes data from animal studies and three phases of controlled clinical trials on human subjects.
The U.S. Postmarketing Safety Assessment System The postmarketing safety assessment system consists of basically two methods of data acquisition: postmarketing studies and case reports of adverse drug reactions (ADRs) reported to the FDA under the MedWatch program. The FDA does not require manufacturers to conduct postmarketing studies of their products; it does require manufacturers to report ADRs that come to their attention, but healthcare providers are not required to report ADRs to the FDA or to the drug manufacturers. Manufacturers sometimes
Resnik
Page 2
Author Manuscript
voluntarily agree to conduct postmarketing studies, but less than half of these studies are brought to completion, and the data are often not analyzed.9 Manufacturers may unreasonably delay or block publication of their own or other scientists’ research that is unfavorable to their products, which happened in the Vioxx case mentioned above.10 In addition, postmarketing studies lack the rigor of premarketing studies. They are often not randomized and lack a control group. The focus of many postmarketing studies is on comparing the manufacturer’s drug to competing drugs or testing it for off-label use, rather than on gathering safety data for the drug.
Author Manuscript
The MedWatch system includes a database of unsolicited case reports of ADRs submitted to the FDA by drug manufacturers or healthcare providers (e.g., physicians, dentists, pharmacists, nurses). This system has numerous methodological shortcomings: Reporting is sporadic, potentially biased, and sometimes incomplete, and the case reports often do not conform to required formats. Healthcare providers are the primary source of ADR data for the pharmaceutical companies. Since reporting of ADRs by healthcare providers is voluntary, underreporting is a major concern.11 According to the FDA, only about 1% of serious ADRs are reported.12 There are at least two reasons why health providers under-report ADRs. First, there is no financial incentive: reporting is purely voluntary. It takes time to fill and submit an ADR, and time is money in a busy clinical practice. Second, healthcare providers might have difficulty recognizing ADRs, due to confusion about applying the definition of an ADR to particular cases.
Author Manuscript
The World Health Organization (WHO) defines an ADR as “any response to a drug which is noxious and unintended, and which occurs at doses normally used in humans for prophylaxis, diagnosis, or therapy of disease, or for the modification of physiological function.”13 This definition is vague and can include common complaints and ailments, most of which are “noxious and unintended.” The source of the ailment, whether medically related or due to an ADR, is often difficult to discern. Healthcare providers do not have the time and resources to investigate every medical problem they encounter as a possible ADR. For example, if a 72-year-old male is having a myocardial infarction (MI), an emergency room physician will probably view this as simply a case of an MI, not as a possible ADR. Other common problems like shortness of breath, cancer, dementia, and diabetes probably would not be reported as ADRs.
Author Manuscript
Postmarketing Safety Worldwide Postmarketing studies and case reporting of ADRs have some problems in common. First, there is insufficient international cooperation concerning postmarketing drug safety. The WHO’s drug safety monitoring program covers 86 countries, but each country has its own system for regulating drugs.14 Although all 86 countries have access to the WHO’s drug safety database, they can choose to ignore the data when deciding whether to approve, withdraw, or place additional warnings on a drug.
Monitor (Assoc Clin Pharmacol). Author manuscript; available in PMC 2015 April 13.
Resnik
Page 3
Author Manuscript
Clearly, international autonomy is important for drug safety, as each country must weigh the risks and benefits of certain drugs for their own populations. However, greater communication among the different nations would benefit all. Thalidomide, which was used as a treatment for morning sickness during pregnancy, is a case in point. Thalidomide was approved for this use in more than 50 countries in the 1950s and 1960s. In contrast, the U.S. chose not to approve thalidomide for this use, citing a lack of adequate safety data. Thousands of children outside the U.S. suffered severe birth defects from exposure to thalidomide in utero before it was finally withdrawn from the international market.15 Better communication between these countries and the U.S. might have prevented some of these birth defects.
Author Manuscript
Second, neither postmarketing studies nor case reporting of ADRs are designed to assess the long-term risks of drugs. A long-term study can last five years or more.16 Postmarketing studies usually last only two years at most, and many are not brought to completion. Although case reporting of ADRs related to a drug can last indefinitely, case reporting is not a systematic, controlled investigation of the effects of the drug. Case reports are, at best, anecdotal evidence of drug risks. As one critic notes, “A plurality of anecdotes is not data.”17
The Need for Long-Term Studies
Author Manuscript
Long-term studies of drugs can be a valuable source of data for drug safety assessment, since ADRs sometimes materialize only after a patient has been taking a drug for years. For example, the association between hormone replacement therapy and increased cancer risk was discovered only after women had been taking the medications for many years.18 It is not unusual for chemical toxicity to manifest clinically after 10, 15, or 20 or more years of continuous exposure or even many years after a single exposure.19 For example, the average age of onset for lung cancer for pack-a-day smokers is 60 years old.20 Someone who inhales asbestos particles while working at a construction site many not develop mesothelioma for 20 years or more.21
Author Manuscript
An example of a well-designed, long-term drug study that demonstrates the usefulness of postmarketing drug safety research is the research conducted by the Data Collection on Adverse Events of Anti-HIV Drugs (DAD) Study Group. This was a prospective observational study of HIV patients. Data were collected on the incidence of myocardial infarction (MI) and exposure to various HIV medications, controlling for age, sex, bodymass index, blood pressure, smoking status, blood cholesterol levels, and other factors that affect the risk of MI. The investigators found that the patients who took protease inhibitors for six or more years had four times the risk of an MI, compared to those who did not take these drugs. In contrast, nonnucleoside reverse-transcriptase inhibitors did not increase the risk of MI.22 The effect detected by the DAD study group would not have been noticeable based on case reporting alone, because most clinicians would not have recognized the MI as an ADR. Although long-term studies of drugs can provide important information for regulators, healthcare providers, and patients, there are financial, practical, and ethical issues to be
Monitor (Assoc Clin Pharmacol). Author manuscript; available in PMC 2015 April 13.
Resnik
Page 4
Author Manuscript
considered, especially for interventional controlled clinical trials that last five or more years. Therefore, many long-term drug safety studies are based on an observational research design, such as prospective or retrospective case-control or cohort studies.23 Observational designs have their own problems:
Author Manuscript
•
Identifying potential confounders is difficult, and if they are not controlled for, they can cause study bias and misleading results. Consider a long-term drug safety study with elderly patients; potential confounders for declining health might include increasing age or natural disease progression, and both must be controlled for.24
•
Drug safety studies are often conducted at multiple study centers, so data collection, management, and analysis can be problematic.
•
Maintaining contact with subjects for long-term follow-up is needed to minimize attrition; comprehensive follow-up requires study commitment from both the investigators and the subjects.
•
Long-term observational studies are expensive, due to the large numbers of subjects needed for adequate statistical power (e.g., 5,000 or more); the DAD study, for example, enrolled more than 23,000 subjects.
Author Manuscript
Funding long-term drug safety studies is perhaps the biggest challenge of all. Pharmaceutical companies are not likely to pay for long-term drug studies unless required to do so by regulatory agencies. As noted earlier, pharmaceutical companies often fail to complete postmarketing studies, even when they voluntarily agree to conduct them. Government research funding agencies, such as the National Institutes of Health (NIH), already have tight budgets, and spending is often influenced by various special interest groups representing patients, disease foundations, healthcare providers, researchers, and others. The NIH uses the disease burden concept to guide funding allocation decisions. One way to convince the NIH to fund more long-term studies of drugs is to demonstrate that ADRs impose a high disease burden on society. There is solid evidence of this, since each year ADRs kill an estimated 100,000 people and seriously injure 2 million.25
Author Manuscript
Perhaps the best way to fund long-term drug studies is to establish public-private partnerships. To ensure independence, companies would not design and fund studies of their own drugs. Instead, they would contribute money to a common funding pool, which would also include money from the NIH and other parties with a vested interest, such as Medicare. The results of the studies would be reported to regulatory agencies and published. To maximize the return on this research investment, it would be wise to focus, at first, on common diseases that are likely to involve many years of pharmacotherapy, such as arthritis, diabetes, gastric reflux, asthma, attention deficit disorder, and depression. Rarer diseases could be tackled later.
Acknowledgments This article is based on a previously published article: Resnik D. 2007. Beyond post-marketing studies and MedWatch: long-term studies of drug safety. Drug Design, Development and Therapy 1: 1–5.
Monitor (Assoc Clin Pharmacol). Author manuscript; available in PMC 2015 April 13.
Resnik
Page 5
Author Manuscript
This research was supported by the National Institute of Environmental Health Sciences, National Institutes of Health. It does not represent the opinions of the National Institute of Environmental Health Sciences or the National Institutes of Health. The author is grateful to Pat Chulada for helpful comments.
References
Author Manuscript Author Manuscript Author Manuscript
1. Couzin J. Gaps in the safety net. Science. 2005; 307:196–198. [PubMed: 15653480] 2. Prakash S, Valentine V. Timeline: the rise and fall of Vioxx. 2006Accessed May 21, 2007NPR.org, June 8, 2006. Available at www.npr.org/templates/story/story.php?storyId=5470430 3. Guthrie P. US Senate passes FDA Revitalization Act. Canadian Medical Association Journal. 2007; 177:23. [PubMed: 17606930] 4. Institute of Medicine. The Future of Drug Safety: Promoting and Protecting the Health of the Public. Washington: Institute of Medicine; 2006. Available at www.nap.edu/catalog/11750.html#toc [Accessed October 11, 2006] 5. Angell, M. The Truth about Drug Companies. New York: Random House; 2004. 6. Strom B. How the US drug safety system should be changed. Journal of the American Medical Association. 2006; 295:2072–2075. [PubMed: 16670415] 7. Ray W, Stein C. Reform of drug regulation: beyond an independent drug-safety board. New England Journal of Medicine. 2006; 354:194–201. [PubMed: 16407517] 8. Strom. 2006:2072. 9. Fontanarosa P, Rennie D, DeAngelis C. Postmarketing surveillance–lack of vigilance, lack of trust. Journal of the American Medical Association. 2004; 292:2647–2650. [PubMed: 15572723] 10. Resnik, D. The Price of Truth. New York: Oxford University Press; 2007. 11. Strom. 2006:2072. 12. US Food and Drug Administration. [Accessed November 9, 2007] The clinical impact of adverse event reporting. Available at www.fda.gov/medwatch/articles/medcont/postrep.htm 13. Requirements for adverse reaction reporting. Geneva: WHO; 1975. World Health Organization (WHO). 14. World Health Organization (WHO). [Accessed November 10, 2007] The safety of medicines. Available at www.who.int/mediacentre/factsheets/fs293/en/index.html 15. Knightley, P.; Evans, H.; Potter, E.; Wallace, M. Suffer the Children: The Story of Thalidomide. New York: The Viking Press; 1979. 16. Resnik D. Beyond post-marketing studies and MedWatch: long-term studies of drug safety. Drug Design, Development and Therapy. 2007; 1:1–5. 17. Strom. 2006:2072. 18. Ray, Stein. 2006:195. 19. Cranor, C. Toxic Torts. Cambridge: Cambridge University Press; 2006. 20. Rhode Island Cancer Council. Lung Cancer: The Facts. Accessed November 9, 2007Available at www.ricancercouncil.org/cancer-info/lung-cancer-facts.php 21. National Cancer Institute. [Accessed: November 9, 2007] Asbestos Exposure: Questions and Answers. Available at www.cancer.gov/cancertopics/factsheet/Risk/asbestos 22. Friis-Møller N. the DAD Study Group. Class of antiretroviral drugs and the risk of myocardial infarction. New England Journal of Medicine. 2007; 356:1723–1735. [PubMed: 17460226] 23. Resnik. 2007:3. 24. Hughes M, Williams P. Challenges in using observational studies to evaluate adverse effects of treatment. New England Journal of Medicine. 2007; 356:1705–1707. [PubMed: 17460224] 25. Public Citizen. [Accessed November 9, 2007] Adverse drug reactions. 2007. Available at www.worstpills.org/public/page.cfm?op_id=4
Monitor (Assoc Clin Pharmacol). Author manuscript; available in PMC 2015 April 13.
Resnik
Page 6
Author Manuscript
Biography David B. Resnik, JD, PhD, is a bioethicist and IRB vice-chair at the National Institute of Environmental Health Sciences, National Institutes of Health. He has published six books and 130 articles on ethical, philosophical, and legal issues in science, technology, and medicine, and is an associate editor for the journal Accountability in Research. He can be reached at [email protected].
Author Manuscript Author Manuscript Author Manuscript Monitor (Assoc Clin Pharmacol). Author manuscript; available in PMC 2015 April 13.
