Closing the information gap: Informing better medical decisionmaking through the use of post-market safety and comparative effectiveness information

Food and Drug Law Journal

Volumn 67, Issue 1, 2012, Pages

  Fox, Bethany ^a  

^a NONE

Author keywords

[No Author keywords available]

Indexed keywords

ADVERSE OUTCOME; COMPARATIVE STUDY; DRUG EFFICACY; DRUG INFORMATION; DRUG LEGISLATION; DRUG SAFETY; FOOD AND DRUG ADMINISTRATION; HUMAN; MEDICAL DECISION MAKING; POSTMARKETING SURVEILLANCE; PRESCRIPTION; REVIEW;

COMPARATIVE EFFECTIVENESS RESEARCH; DECISION MAKING; HUMANS; PRODUCT SURVEILLANCE, POSTMARKETING; UNITED STATES;

EID: 84864115269     PISSN: 1064590X     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Review

References (147)

1. The Institute of Medicine defines CER as "the generation and synthesis of evidence that compares the benefits and harms of alternative methods to prevent, diagnose, treat, and monitor a clinical condition or to improve the delivery of care. The purpose of CER is to assist consumers, clinicians, purchasers, and policy makers to make informed decisions that will improve health care at both the individual and population levels." Institute of Medicine, Initial National Priorities for Comparative Effectiveness Research, 2009, at 29 [hereinafter IOM - CER Report].
2. "Active surveillance" as applied to postmarket medical product surveillance refers to a system that permits FDA to "initiate its own safety evaluations that use available electronic healthcare data to investigate the safety of medical products." FDA, The Sentinel Initiative: Access to Electronic Healthcare Data for More Than 25 Million Lives, July 2010, at 2 [hereinafter Sentinel Report].
3. 21 U.S.C § 355(k)(3)(C)(i)(III) (2006).
4. FDA defines "clinical trial" as any prospective investigations in which the applicant or investigator determines the method of assigning the drug product(s) or other interventions to one or more human subjects. "Studies" are all other investigations, such as investigations with humans that are not clinical trials as defined above (e.g., observational epidemiologic studies), animal studies, and laboratory experiments. FDA, Draft Guidance for Industry: Postmarketing Studies and Clinical Trials - Implementation of Section 505(o) of the Federal Food, Drug, and Cosmetic Act, July 2009, at 4.
5. 21 U.S.C. § 355(o)(3) (2006).
6. ARRA, Pub. L. No. 111-5, 111th Cong., 1st Sess., 123 Stat. 115, 176-77 (Feb. 17, 2009).
7. PPACA, Pub. L. No. 111-148, 124 Stat. 119 (Mar. 23, 2010). The PPACA provides for the creation of the PCORI as a nonprofit corporation that is "neither an agency nor establishment of the United States Government." PPACA Sec. 6301, 124 Stat. 119, 728 (to be codified at 42 U.S.C. §1320e(b)(1)). The purpose of the PCORI is to facilitate "informed health decisions by advancing the quality and relevance of evidence" by research and the "dissemination of research findings with respect to the relative health outcomes [and] clinical effectiveness" of various healthcare interventions. Id. § 1320e(c).
8. Institute of Medicine, The Future of Drug Safety: Promoting and Protecting the Health of the Public, 2006, at 37 [hereinafter IOM - Drug Safety Report].
9. Important to note is the difference between efficacy and effectiveness: "effectiveness" refers to the extent to which a therapy does what it is intended to do when used under real-world circumstances, while "efficacy" is the extent to which an intervention produces a beneficial result under controlled conditions.
10. See IOM - CER Report, supra note 1 at 38.
11. IOM - CER Report, supra note 1 at 31.
12. See IOM - Drug Safety Report, supra note 8 at 38 ("Trials often exclude patients with comorbidities or those taking other medications, although both may be very common among future users of the marketed drugs.").
13. See id. ("Preapproval clinical trials have little information on the effects of long-term exposure to the drug due to their often short duration.").
14. Id.
15. See id. at 36-37 (stating that phase 3 trials can involve fewer than 100 patients or many thousands, but on average involve about 600-3,000 patients; and clinical trials usually take 2-10 years to complete).
16. Id. at 37.
17. See id. at 38 (sponsors are not routinely required to submit comparative trials to obtain approval); see also IOM - CER Report, supra note 1 at 51 (head-to-head studies may be necessary if comparison to placebo is unethical).
18. James Dabney Miller, The Patient-Centered Outcomes Research Institute, Vol. 4, No. 1, J. Health & Life Sci. L., October 2010, at 2;
19. but see IOM - CER Report, supra note 1 at 51-52 (finding an incentive for comparative research where sponsors are pressured to conduct CER to obtain reimbursement on a specific formulary tier or seek a superiority claim in subsequent marketing for the product).
20. Miller, supra note 17 at 2;
21. Christopher P. Cannon et. al., Intensive Versus Moderate Lipid Lowering with Statins After Acute Coronary Syndromes, 350 New Eng. J. Med. 1495 (2004).
22. Id.
23. IOM - CER Report, supra note 1 at xiii.
24. Thomas N. Tiedt, The Drug Safety System Conundrum, 62 Food Drug L.J. 547, 547 (2007).
25. See Stephanie Saul, Heart Attack Risk Seen in Drug for Diabetes, The New York Times, May 22, 2007;
26. see also Reuters, A Time Line of Vioxx, The New York Times, Aug. 19, 2005. Both agents were approved in 1999; problems with Avandia surfaced in May 2007. The extent of Vioxx's cardiovascular problems came to light in 2004, after which the drug was promptly withdrawn. Id.
27. IOM - CER Report, supra note 1 at 30.
28. Safety signals are potential relationships between drug use and adverse events, which are sometimes the first indicator of a potential drug safety problem. U.S. Government Accountability Office, Drug Safety: FDA Has Begun Efforts to Enhance Postmarket Safety, but Additional Actions Are Needed, Nov. 2009, at 8 n.22 [hereinafter GAO 2009 Report].
29. See IOM - CER Report, supra note 1 at xv (describing how the committee narrowed down over a thousand potential topics for comparative effectiveness research to their list of 100 "highest priority" research recommendations).
30. U.S. Government Accountability Office, Drug Safety: Improvement Needed in FDA 's Postmarket Decisionmaking and Oversight Process, March 2006, at 9-10 [hereinafter GAO 2006 Report].
31. See 21 C.F.R. § 314.80 (2010).
32. See id. (defining a serious adverse drug experience as "[a]ny adverse drug experience occurring at a dose that results in any of the following outcomes: death, a life-threatening adverse drug experience, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant disability/incapacity, or a congenital anomaly/birth defect").
33. Id.
34. IOM - Drug Safety Report, supra note 8 at 54.
35. See Tiedt, supra note 21 at 555 ("Some adverse drug reaction cases represent predictable consequences of the drug's known pharmacology and expected toxicity");
36. see also GAO 2006 Report, supra note 26 at 26-27 (clinical trials are a source of information useful for the evaluation of postmarket drug safety issues);
37. IOM - Drug Safety Report, supra note 8 at 35 ("the regulators may look for possible markers of safety problems ... on the basis of ... questions about the class of drugs").
38. GAO 2009 Report, supra note 24 at 9, Table 1.
39. "Passive surveillance" refers to a safety monitoring program that relies on external sources to report suspected medical product-related adverse events. Sentinel Report, supra note 2 at 2.
40. See GAO 2006 Report, supra note 26 at 25 (describing the difficulty in determining a causal relationship between Vioxx and cardiovascular adverse events, in part because of the "relatively high rate of cardiovascular events among the elderly").
41. See id. ("AERS reports may be confounded by other factors");
42. see also Roselie A. Bright, Strategy for Surveillance of Adverse Drug Events, 62 Food & Drug L. J. 605, 609 (2007) (a time delay may prevent a causal connection between the drug and the event).
43. See GAO 2006 Report, supra note 26 at 26-27 (clinical trials are a source of information useful for the evaluation of postmarket drug safety issues);
44. see also IOM - Drug Safety Report, supra note 8 at 35 ("the regulators may look for possible markers of safety problems ... on the basis of ... questions about the class of drugs or the mechanism of action.").
45. Id.
46. The NIH defines data mining as the application of statistical techniques, e.g. predictive modelling, clustering, link analysis, deviation detection and disproportionality measures, to databases. See http://www. ncbi.nlm.nih.gov/pmc/ articles/PMC1884444/.
47. GAO 2009 Report, supra note 24 at 27.
48. IOM - Drug Safety Report, supra note 8 at 54 ("FDA is making limited use of data mining software to identify early drug signals");
49. GAO 2009 Report, supra note 24 at 27 ("FDA is developing a new database ... that should offer integrated data analysis features to facilitate the identification of safety issues.").
50. IOM - Drug Safety Report, supra note 8 at 55.
51. 21 U.S.C. § 355(k)(3)(B) (2006).
52. See Sentinel Report, supra note 2 at 2 (Sentinel Initiative will "enhance the understanding of medical product safety" and, in combination with passive surveillance, will provide "more comprehensive means" for monitoring drug safety).
53. Id.
54. GAO 2009 Report, supra note 24 at 30.
55. In observational studies, the investigator does not control the therapy, but observes and evaluates ongoing medical care, in contrast, in clinical trials the investigator controls the therapy to be received by participants and can test for causal relationships. GAO 2006 Report, supra note 26 at 7 n.11.
56. See IOM - CER Report, supra note 1 at 148.
57. See id. (observational studies are typically most appropriate for answering questions related to prognosis, diagnostic accuracy, incidence, prevalence, and etiology).
58. Barbara J. Evans, Authority of the Food and Drug Administration to Require Data Access and Control Use Rights in the Sentinel Data Network, 65 Food & Drug L.J. 67, 96 (2010).
59. See remarks by Dr. L. Allen Dobson Jr., The Brookings Institution, Using Data to Support Better Health Care: One Infrastructure with Many Uses, Dec. 2, 2009, at 33-34, transcript available for download at http://www.brookings.edu/ events/2009/1202-health-care-data.aspx [hereinafter Brookings Institution Program];
60. see also Miller, supra note 17 at 4 (in an observational study, the investigators observe patients either prospectively or retrospectively).
61. See Tiedt, supra note 21 at 553 ("While only a few thousand patients are exposed to the new drug in aggregate before approval, millions of patients, many of whom have significantly more complex medical histories than those studied prior to approval, will ultimately use the drug in intended as well as untested circumstances after approval");
62. see also Miller, supra note 17 at 3 ("A common theme in CER is the distinction between the effectiveness of a medical ... intervention on the one hand, and the efficacy of that intervention on the other ... A drug may be found to exhibit efficacy compared to a placebo in a clinical trial but may not be effective in treating disease in the general population.").
63. See GAO 2009 Report, supra note 24 at 9, Table 1 (noting the weaknesses of observational studies). 53 Id.
64. IOM - CER Report, supra note 1 at 148.
65. See Carol C. Diamond, et. al., Collecting and Sharing Data for Population Health: A New Paradigm, Health Aff., July/Aug. 2009, at 454 (health data are often "dirty - incomplete, inconsistent, or wrong");
66. see also IOM - CER Report, supra note 1 at 150-51 (claims data from payors is often missing patient information; clinical data is limited by restrictive drug formularies).
67. PPACA § 6301, 124 Stat. 119, 735 (to be codified at § 1320(e)(d)(2)(A)).
68. 21 U.S.C. § 355(o)(3) (2006).
69. Id.
70. Id. FDA Guidance defines new safety information as information derived from a clinical trial, an adverse event report, a post-approval study, or peer-reviewed biomedical literature; data derived from the postmarket risk identification and analysis system; or other scientific data deemed appropriate by the Secretary about (A) a serious risk or unexpected serious risk associated with use of the drug that the Secretary has become aware of; or (B) the effectiveness of the approved risk evaluation and mitigation strategy for the drug. FDA, Draft Guidance for Industry: Postmarketing Studies and Clinical Trials - Implementation of Section 505(o) of the Federal Food, Drug, and Cosmetic Act, July 2009, at 12.
71. IOM - Drug Safety Report, supra note 8 at 56.
72. See IOM - CER Report, supra note 1 at 149 (discussing the benefit of using existing data, such as claims data or electronic health records from integrated health systems, to enhance the timeliness and value of CER).
73. See IOM - Drug Safety Report, supra note 8 at 56 (discussing the difficulties FDA experiences when they conduct their own observational studies).
74. See IOM - CER Report, supra note 1 at 151 (comparative effectiveness researchers face difficulties in securing claims data, which "often requir[es] inquiries to multiple states and their Institutional Review Boards").
75. Id. at 150.
76. Id. at 151.
77. See Sentinel Report, supra note 2 at 1-3 (discussing the process by which FDA will request information for collaborating institutions about the safety of medical products and the benefits of the active surveillance system).
78. See IOM - CER Report, supra note 1 at 153 (in the CER context, a single database may not provide enough patients or enough information about a patient's condition or medical history; "several complementary datasets may be needed to meet the needs of CER.").
79. Sentinel Report, supra note 2 at 1.
80. Id.
81. Evans, supra note 49 at 96.
82. See remarks by Mark B. McClellan, Brookings Institution Program, supra note 50 at 7-8 (discussing the similar evidentiary needs for healthcare infrastructure to answer safety and comparative effectiveness questions. To address a safety query, measurements of the treatments that were provided, the outcomes, and any potential patient-level confounders are required for a well-defined sample of patients. For comparative effectiveness questions, the same type of information on treatments, clinical outcomes and potential confounders is solicited for the product in question and the relevant treatment[s] of comparison.).
83. See Sentinel Report, supra note 2 at 8 ("we are careful not to lose sight of [Sentinel's] potential value to other public and private entities.").
84. 21 U.S.C. § 355(k)(3)(C)(i)(I) (2006).
85. Sentinel Report, supra note 2 at 8 (emphasis added);
86. see also Evans, supra note 49 at 97-102 (discussing pathways for granting Sentinel Network use rights, and indications that outside use rights are being contemplated).
87. PPACA § 6301, 124 Stat. 119, 735 (to be codified at § 1320e(d)(2)(B)(i)(II)).
88. IOM - CER Report, supra note 1 at 153. The IOM Report also details the need for CER data to be linked "at the individual patient level from multiple large-scale, clinical research networks ... A single database may not provide a large enough patient cohort or a sufficiently complete picture of a patient's condition or health history, whereas several complementary datasets may be needed to meet the needs of CER." The report further outlines the process of linking information across datasets for CER purposes, and identifies FDA's Sentinel Initiative as "the most ambitious linkage proposal to date." Id.
89. FDA, Draft Guidance for Industry: Postmarketing Studies and Clinical Trials - Implementation of Section 505(o) of the Federal Food, Drug, and Cosmetic Act, July 2009, at 4.
90. See GAO 2006 Report, supra note 26 at 25 (clinical trials are "considered the gold standard" for assessing evidence about safety and efficacy");
91. see also GAO 2009 Report, supra note 24 at 9, Table 9 (noting the clarity provided by randomized clinical trials).
92. IOM - CER Report, supra note 1 at 147.
93. Id. 81 Id. 82 Id.
94. GAO 2006 Report, supra note 26 at 26-27.
95. Id.
96. See IOM - Drug Safety Report, supra note 8 at 38 (sponsors are not usually required to submit comparative trials to obtain approval, and sponsors do not usually initiate such trials unless they believe that the research results will be favorable).
97. IOM - CER Report, supra note 1 at 148.
98. Id.
99. 21 U.S.C. § 355-(o)(3) (2006) (authorizing FDA to require postmarketing clinical trials to assess a known serious risk or signals of a serious risk related to the use of the drug or to identify an unexpected serious risk when available data indicate the potential for a serious risk, but requiring FDA to find that a postmarketing study will not be sufficient address the safety risk).
100. There is evidence that commercially-funded trials are more likely than publicly financed trials to produce favorable results. Some critics claim that this is due to sponsor's intentional design of methodologically inferior trials. FDA oversight of clinical trials should mitigate a sponsor's ability to design a trial that is insufficient to answer the outstanding safety question.
101. See Benjamin P. Falit, Curbing Industry Sponsors' Incentive to Design Post-Approval Trials that are Suboptimal for Informing Prescribers but More Likely than Optimal Designs to Yield Favorable Results, 37 Seton Hall L. Rev. 969 (2007).
102. See IOM - Drug Safety Report, supra note 8 at 38 (sponsors are not routinely required to submit comparative trials to obtain approval);
103. see also IOM - CER Report, supra note 1 at 51 (head-to-head studies may be necessary if comparison to placebo is unethical).
104. See IOM - CER Report, supra note 1 at 146-47 ("Fundamental questions of comparative effectiveness often require head-to-head comparisons ... using randomized assignment").
105. Id. at 147.
106. Requirements on Content and Format of Labeling for Human Prescription Drug and Biological Products, 71 Fed. Reg. 3921, 3934 (Jan. 24, 2006) [hereinafter Labeling Preamble].
107. 21 U.S.C. § 321 (2006).
108. Labeling Preamble, supra note 93 at 3964, 3967.
109. 21 C.F.R. § 201.57(c)(5) (2010).
110. Id. § 201.57(c)(7).
111. Labeling Preamble, supra note 93 at 3934.
112. FDA, Guidance for Industry: Drug Safety Information - FDA's Communication to the Public, March 2007, at 8-10.
113. Labeling Preamble, supra note 93 at 3938-39.
114. Id. at 3937-38.
115. FDA, Guidance for Industry: Clinical Studies Section ofLabelingfor Human Prescription Drug and Biological Products - Content and Format, Jan. 2006, at 2 ("[The Clinical Studies] section of the labeling is not intended to describe all available effectiveness data. Additional studies that reach the same conclusion should be omitted or described briefly without detail.")
116. By wav of comparison, risk information need be far less substantiated to be included on the label, though nonetheless a real and not speculative possibility. In most cases, "risk information in Highlights would be based on clinical data," though "risk information derived from animal data could be appropriate" for inclusion in the label. Labeling Preamble, supra note 93 at 3939.
117. 21 C.F.R. § 201.56(a)(3) (2010).
118. FDA, Guidance for Industry: Clinical Studies Section of Labeling for Human Prescription Drug and Biological Products - Content and Format, Jan. 2006, at 2-3.
119. 21 C.F.R. § 201.56(a)(3) (2010);
120. FDA, Guidance for Industry: Clinical Studies Section of Labeling for Human Prescription Drug and Biological Products - Content and Format, Jan. 2006, at 2-3.
121. Labeling Preamble, supra note 93 at 3972.
122. Id. at 3934.
123. 21 U.S.C. § 355(o)(4) (2006).
124. See FDA, Guidance for Industry: Drug Safety Information - FDA 's Communication to the Public, March 2007, at 8;
125. see also MedWatch Partners: The FDA Safety Information and Adverse Event Reporting Program, available at http://www.fda.gov/Safety/MedWatch/ucm170520.htm (last updated October 18, 2010). MedWatch Partners are a variety of professional medical associations, such as the American Medical Association or American Academy of Pediatrics. The Partners work with FDA to help keep their members informed about medical product safety information and reporting. Id.
126. FDA, Guidance for Industry: Drug Safety Information - FDA 's Communication to the Public, March 2007, at 10.
127. 21 U.S.C. § 321 (2006).
128. See FDA, Guidance for Industry: Presenting Risk Information in Prescription Drug and Medical Device Promotion, May 2009, at 1, 3 n.9 (recommendations for presentation of risk information apply to promotions directed to healthcare professionals and consumers; promotional materials include television ads, brochures, booklets, detailing pieces, internet web sites, print ads, exhibits, and sound recordings or radio ads).
129. See Lars Noah, Death of a Salesman: To What Extent Can the FDA Regulate the Promotional Statements of Pharmaceutical Sales Representatives?, 47 Food & Drug L.J. 309, 310-11 (1992) (explaining the role of pharmaceutical sales representatives in conveying drug information to physicians with article reprints, samples, and verbal communications. The government's Dictionary of Occupational Titles defines "pharmaceutical detailer" as an employee who "promotes use of and sells ethical drugs and other pharmaceutical products to physicians ... using knowledge of medical practices, drugs, and medicines: Calls on customers, informs customers of new drugs, and explains characteristics and clinical studies conducted with drug. Discusses dosage, use, and effect of new drugs and medicinal preparations.").
130. Noah, supra note 114 at 317 (quoting Kessler & Pines, The Federal Regulation of Prescription Drug Advertising and Promotion, 264 J.A.M.A. 2409, 2411 (1990)).
131. See 21 C.F.R. § 202.1(e)(5)(ii) (2010). 117 Id. § 202.1(e)(6)(1). 118 Id. § 202.1(e)(4)(ii)(c).
132. Warning Letter to Joseph Pieroni, CEO of Sankyo Pharma, Inc., Jan. 6,2006, available for download at http://www.fda.gov/Drugs/ GuidanceComplianceRegulatoryInformation/EnforcementActivitiesbyFDA/ WarningLettersandNoticeofViolationLetterstoPharmaceuticalCompanies/ucm053258. htm.
133. Noah, supra note 114 at 309 ("Personal visits by salespersons remain one of the most effective means for bringing new drugs to the attention of prescribers, and for maintaining prescriber interest in drugs which have been on the market for an extended period of time.");
134. see also Adriane Fugh-Berman and Shahram Ahari, Following the Script: How Drug Reps Make Friends and Influence Doctors, PloS Med 4(4): e150 (April 24, 2007), available at http://www.plosmedicine.Org/article/info:doi/10.1371/joumal. pmed.0040150 ("Physicians view drug information provided by reps as a convenient, if not entirely accurate, educational service.").
135. See Fugh-Berman, supra note 120 ("Pharmaceutical companies spend billions of dollars annually to ensure that physicians most susceptible to marketing prescribe the most expensive, most promoted drugs to the most people possible.").
136. See Noah, supra note 114 at 309-10 (critics have charged that verbal claims made by detailers may lack fair balance, make unsubstantiated product claims, or suggest unapproved uses);
137. see also Fugh-Berman, supra note 120 ("Whether or not physicians believe in the accuracy of information provided, detailing is extremely effective at changing prescribing behavior");
138. Puneet Manchanda & Elisabeth Honka, The Effects and Role of Direct-to-Physician Marketing, 5 Yale J. Health Pol'y, L. & Ethics 785, 808-09 (2005) (an "overemphasis of drug promotion versus information delivery ... engender[s] negative attitudes" among physicians).
139. See IOM - CER Report, supra note 1 at 159 ("The CER Program should require researchers to publish all federally funded CER studies and make the research readily available to the public.");
140. see also Paul H. Keckley & Barbara B. Frink, Comparative Effectiveness: A Strategic Perspective on What It Is and What It May Mean for the United States, Vol. 3, No. 1, J. Health & Life Sci. L. 53, Exh. 1 (Oct. 2009) (strategies for dissemination include print/web publication, scientific and clinical practice journals, professional practice standards, association literature, and health information technology software).
141. See Labeling Preamble, supra note 93 at 3968. 123 Id. at 3934.
142. See FDA, Guidance for Industry: Clinical Studies Section of Labeling for Human Prescription Drug and Biological Products - Content and Format, Jan. 2006, at 2-3 (explicit claims of superiority must be supported by substantial evidence, which would include adequate and well-controlled trials specifically designed to establish the superiority of one treatment over the other).
143. See id.
144. See RxFacts.org, the Independent Drug Information Service, available at http://www.rxfacts.org/ detailing.php;
145. see also Editorial, Countering the Drug Salesmen, The New York Times, March 20, 2008.
146. Id. Academic detailing legislation has been introduced in Washington D.C., Pennsylvania, and Massachusetts.
147. 21 C.F.R. § 202.1(e)(6)(1) (2010).