The risk of risk reduction: Can postmarket surveillance pose more risk than benefit?

Food and Drug Law Journal

Volumn 62, Issue 3, 2007, Pages 473-492

  Hall, Ralph F ^a,b,c,d  

^a UNIVERSITY OF MINNESOTA LAW SCHOOL   (United States)

^b Baker and Daniels LLP   (United States)

^c Baker and Daniels LLP   (United States)

^d MR3 Medical LLC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ROFECOXIB; ROSIGLITAZONE; SEROTONIN UPTAKE INHIBITOR; ANTIEMETIC AGENT; DOXYLAMINE;

CLINICAL RESEARCH; DECISION MAKING; DEFIBRILLATOR; DEVICE; DRUG APPROVAL; DRUG INDUSTRY; DRUG INFORMATION; DRUG SAFETY; DRUG SCREENING; DRUG SURVEILLANCE PROGRAM; FOOD AND DRUG ADMINISTRATION; HEALTH CARE; HUMAN; POLICY; POSTMARKETING SURVEILLANCE; REVIEW; RISK BENEFIT ANALYSIS; RISK REDUCTION; UNSPECIFIED SIDE EFFECT; ARTICLE; DRUG LEGISLATION; EQUIPMENT; FEMALE; INFORMATION PROCESSING; INTERPERSONAL COMMUNICATION; LEGAL ASPECT; MALE; METHODOLOGY; PREGNANCY; RISK MANAGEMENT; SAFETY; UNITED STATES;

ANTIEMETICS; DATA COLLECTION; DEFIBRILLATORS, IMPLANTABLE; DEVICE APPROVAL; DISCLOSURE; DOXYLAMINE; DRUG APPROVAL; DRUG INDUSTRY; EQUIPMENT SAFETY; FEMALE; HUMANS; LEGISLATION, DRUG; MALE; PREGNANCY; PRODUCT SURVEILLANCE, POSTMARKETING; RISK MANAGEMENT; SEROTONIN UPTAKE INHIBITORS; UNITED STATES; UNITED STATES FOOD AND DRUG ADMINISTRATION;

EID: 35548972100     PISSN: 1064590X     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Review

References (77)

1. For our purposes, the author will use the term "postmarket surveillance" broadly to include activity ranging from anecdotal adverse event reporting to mandated post-approval studies under 21 U.S.C. §§ 356b or 3601.
2. See 21 U.S.C. § 393(b).
3. Throughout this article the author will refer to all such actions as "field safety actions." Any Class I, II or III recall, safety alert or warnings or contraindications added to product labeling as a result of data obtained via postmarket surveillance is included in this term. In essence, for the author's purposes, field safety action refers to any communication or physical product removal in response to a perceived patient issue identified via any postmarket surveillance process. The term does not include new indications, routine updates on product usage or performance, or other routine updates, modifications or changes in product labeling.
4. For the author's purposes, the regulatory differences between drugs, devices and biologics are unimportant. As such, the author simply includes all of these in the discussion.
5. A more complete listing of these communication tools can be found in a recent FDA guidance entitled Drug Safety Information - FDA's Communication to the Public available at http://www.fda.gov/cder/guidance/7477fnl.pdf at p. 6.
6. See, for example, 21 U.S.C. § 334 for FDA's seizure authority and 21 C.F.R. Part 7 for a description of recall activities.
7. One question that has been raised is whether using the term "recall" in these circumstances is wise as that term may lead patients to stop using the product or to seek the removal or explant of an implanted medical device. See http://www.hrsonline.org/Policy/CodingReimbursement/ reimbursement/physician/upload/ HRSpercent20Devicepercent20Performancepercent20Guidelines.pdf at p. 3.
8. See 21 C.F.R. §§ 201.56 and 201.57.
9. Drug Safety Information - FDA's Communication to the Public, http://www.fda.gov/cder/guidance/7477fnl.pdf at p. 3.
10. Id. at p. 5.
11. See, for example, FDA's authority under 21 U.S.C. §§ 355(e) and 360e(e).
12. See 21 C.F.R. § 7.40(a).
13. See Abbott Consent Decree http://www.fda.gov/cdrh/ocd/abbott.html.
14. See 21 U.S.C. § 360j(g).
15. The author is differentiating the postmarket surveillance system from corrective and preventative action (CAPA) systems under, for example, 21 C.F.R. § 820. The postmarket surveillance system results in public information being used to assess performance of already distributed products in order to identify risk reduction opportunities. The CAPA system, on the other hand, is intended to be proactive and use performance information for the design of new products and to address issues in similar products. Clearly the systems are related and the same information may be used to decide whether to trigger a recall and to modify the design of the next generation product.
16. Reviewer Guidance: Evaluating the Risks of Drug Exposure in Human Pregnancy, http://www.fda.gov/cber/gdlns/rvrpreg.pdf at p 16. (emphasis added).
17. See, for example, S. 484 (Kennedy-Enzi) pending in the Senate as of this date (July 17. 2007).
18. Congress is not the only entity advancing such concepts. Other organizations have made similar proposals. See, for example, the Sept. 2006 Institute of Medicine (IOM) report on the future of drug safety available at http://www.iom.edu/CMS/3793/26341/37329.aspx. As of this time (July 17. 2007), the final parameters of such systems are yet to be determined.
19. There are two important differences between using postmarket surveillance to identify inherent but low frequency events and the use of postmarket surveillance to identify product deviations. In this second situation the newness of the product is irrelevant to the post-market surveillance. The existence of a bad lot of a drug or an improperly manufactured device is not directly related to the newness of product. The need to identify unknown product risks generally decrease after several years because by that point in time, the bulk of the data that could not legitimately be learned via the premarket approval clinical studies has been collected. The second purpose of detecting product deviations is designed to protect public health by ongoing or continuous monitoring of product performance to identify deviations from the expected.
20. See 21 U.S.C. §§ 55(d), (e) and 360e(d) and (e).
21. This can be seen in the case of user fees. Adding resources to the approval/review side resulted in what many perceive as a decrease in resources for other activities. See, IOM report available at http://www.iom.edu/CMS/3793/26341/37329.aspx. Paradoxically, one of the areas allegedly suffering from resource limitations due to the increased funding for approval activities has been postmarket studies and postmarket surveillance.
22. It is outside the scope or purpose of this article to identify situations which can be attributed to company misdeeds or mistakes. Field safety actions can be caused as well by situations outside the control of the company.
23. FDA has been roundly criticized by Congress and others in a number of congressional hearings for allegedly failing to discover the Vioxx issues and Avandia issues prior to approval. See, for example, http://oversight. house.gov/story.asp?ID=1325. The author leaves it to others to assess the validity of any such criticism.
24. See, for example, 21 U.S.C. §§ 331-334 and the specific obligation to permit inspections (21 U.S.C. § 331(f)).
25. Note that CDRH's Postmarked Transformation Initiative does include a strong emphasis on enforcement, see http://www.fda.gov/cdrh/postmarket/ mdpi-report-1106.html at p. 21.
26. FDA may, on occasion, informally consider these risks. It is not a formal part of the process has no established criteria and is not generally part of the public debate.
27. 21 C.F.R. Part 7 and 21 C.F.R. § 806.
28. http://www.fda.gov/cder/guidance/7477fnl.pdf at p. 5.
29. See http://www.fda.gov/oc/reports/iom013007.html.
30. See Report of the Postmarket Transformation Leadership Team from Nov. 2006 available at http://www.fda.gov/cdrh/postmarket/mdpi-report- 1106.html.
31. Examples of such professional literature include Cohen and Neumann, What's More Dangerous, Your Aspirin or Your Car? Thinking Rationally about Drug Risks (and Benefits), HEALTH AFFAIRS, No. 26, no. 3 (2007): 636-646
32. and Graham and Hu, The Risk-Benefit Balance in the United States: Who Decides?, HEALTH AFFAIRS No. 26 (2007): 625-635. A detailed assessment of such literature is beyond the author's scope.
33. FDA recently announced the creation of a risk advisory committee to provide expert input to the agency on communication issues and tools, see http://www.fda.gov/bbs/topics/NEWS/2007/NEW01648.html. Likewise, the Heart Rhythm Society (HRS) has advocated improvements in communication tools, http://www.hrsonline.org/Policy/CodingReimbursement/reimbursement/physician/ upload/HRSpercent20Devicepercent20Performancepercent20Guidelines.pdf.
34. See new pharmaceutical labeling regulations and guidance available at 71 Fed. Reg. § 3922 (Jan. 24, 2006) and http://www.fda.gov/cder/guidance/5537fnl.htm.
35. The entire report from the HRS' policy initiative and conference can be found at http://www.hrsonline.org/Policy/CodingReimbursement/reimbursement/ physician/upload/HRSpercent20Devicepercent20Performancepercent20Guidelines.pdf.
36. Id.
37. Id. at p. 15.
38. Id. at p. 5 and references 1-18 on p. 22. The importance of the ICD has been recognized many other places. For example, the inventors were inducted into the National Inventors Hall of Fame in 2002.
39. As stated elsewhere, the author offers no opinion as to appropriateness of the conduct of any party. The author has neither the information nor the desire to enter that battle. Pending lawsuits may well answer these questions.
40. Note that the author worked for Guidant Corporation for a number of years up until 2003. He had no involvement in the product recall issues and has no information other than what is publicly available. No opinion is offered about any issues surrounding these recalls.
41. Barry Meier, Maker of heart Device Kept Flaw from Doctors, NY TIMES, (May 24, 2005).
42. Paul Gould, et al, Complications Associated with Implantable Cardioverter-Defibrillator Replacement in Response to Device Advisories, 295 JAMA, 1907 (2006).
43. See, for example, Press Release, Guidant Initiates Worldwide Physician Communication Regarding Important Safety Information and Corrective Action About Implantable Cardiac Defibrillators (June 24, 2005);
44. Press Release, Guidant Initiates voluntary Physician Advisory on Certain Pacemakers (Sept. 22, 2005);
45. Press Release, Medtronic Issues Physician Advisory Regarding Limited Subset Of Pacemakers (Nov. 29, 2005);
46. Press Release, St. Jude Medical Announces ICD Software Upgrade Notification to Physician Customers (June 20, 2005) for examples of various safety alerts including the rate of failure.
47. See, William H. Maisel, Safety Issues Involving Medical Devices, 294 JAMA, 955 (2005),
48. Robert Steinbrook, The controversy over Guidant's Implantable Defibrillators, 353 NEW ENG. J. MED. 221 (2005)
49. and Maura Lerner, Hunting down Dangers to the Heart, STAR TRIB., (July 24, 2005) at 1A.
50. Available at http://www.hrsonline.org/Policy/CodingReimbursement/ reimbursement/physician/upload/ HRSpercent20Devicepercent20Performancepercent20Guidelines.pdf.
51. Paul Gould, et al, Complications Associated with Implantable Cardioverter-Defibrillator Replacement in Response to Device Advisories, 295 JAMA, 1907 (2006).
52. Id. at 1907, emphasis added.
53. This is not an unusual percentage. This death rate is consistent with other studies finding, for example, a 0.5 percent mortality rate with new ICD implants. M.R. Bristow, L.A. Saxon, J. Boehmer, et al., Cardiac- Resynchronization Therapy with or without an Implantable Defibrillator in Advanced Chronic Heart Failure, 350 N ENG. J MED. 2140 (2004).
54. 5.8 percent major complication rate in 18 percent explant rate equates to approximately a 1 percent rate over the total of explants and non-explants.
55. HRS reports similar risks of device explants based upon the Gould report and other data. See http://www.hrsonline.org/Policy/CodingReimbursement/ reimbursement/physician/upload/ HRSpercent20Devicepercent20Performancepercent20Guidelines.pdf at p. 19.
56. All data is taken from each company's most recent publicly available product performance report. Devices selected are those available in 2005 and which have at least 4 years of performance data available. This chart is for illustrative purposes only. Product performance reports can be found at http://www.guidant.com/ppr/pprquarterly.shtml, http://www.medtronic.com/crm/ performance/index.html, and http://www.sjm.com/documents/ppr.pdf.
57. The author is reviewing this situation at a population level. First, that is necessary and appropriate for these types of decisions. Second, one cannot assess the situation of a specific patient. The author has neither the information nor the expertise to do so.
58. The actual process to assess the comparative medical risk is to compare A (the number of defects - number that were or would have been detected prior to any adverse effect - number of defects that occur but do not result in patient harm) against B (number of defects in the new product - number that were or would have been detected prior to any adverse effect - number of defects that occur but do not result in patient harm + harm caused by the replacement surgery). If A is larger than B, then replacement seems warranted.
59. Suicidality is not the same as suicide. Rather, it is thinking about and talking about committing suicide.
60. http://www.fda.gov/cder/drug/antidepressants/SSRIPHA200410.htm.
61. Jeffrey A. Bridge, et al, Clinical Response and Risk for Reported Suicidal Ideation and Suicide Attempts in Pediatric Antidepressant Treatment, 297 JAMA, 1683 (2007).
62. Available at http://www.fda.gov/ohrms/dockets/ac/06/slides/2006- 4272OPH1-13-valuck_files/frame.htm#slide0063.htm. The author recognizes that there is some data suggesting the opposite. Nemeroff, et al. Impact of Publicity Concerning Pediatric Suicidality Data on Physician Practice Patterns in the United States, 64 ARCH. GEN PSYCHIATRY 466 (2007). FDA believes the issue is real. This discrepancy in data also reinforces our position that the impact of field safety actions is not adequately understood.
63. Brady E. Hamilton, et al, Annual Summary of Vital Statistics, 119 PEDIATRICS 345 (2007) at 356-357.
64. [THE PINK SHEET], (May 7, 2007) at 32.
65. http://www.fda.gov/cder/drug/antidepressants/SSRIPHA200410.htm.
66. http://www.fda.gov/bbs/topics/NEWS/2007/NEW01624.html.
67. Much of the controversy was created by the media and others, not directly by FDA. This situation, however, demonstrates the impact of a public controversy about a particular product and identifies a difficult task for FDA. On occasion, FDA will need to publicly respond to a public or media driven controversy. The cynics in the crowd may also assert that another purpose for fueling the public controversy is to attract more plaintiffs for product liability suits and to increase the risk to the manufacturer of such suits in order to drive a faster and more lucrative settlement. While that may have been a purpose or at least an outcome, for the author's purposes the focus is on the more direct public health reasons.
68. See for example, http://www.fda.gov/cder/present/clinpharm2000/ Koren/sld001.htm.
69. 64 FR 43190 (Aug. 9, 1999).
70. C. Ineke Neutel, et al, Variation in Rates of Hospitalization for Excessive Vomiting in Pregnancy by Benedctin/Diclectin use in Canada, http://www.nvp-volumes.org/p1_9.htm at 4.
71. http://www.fda.gov/ohrms/dockets/ac/00/transcripts/3645t1.pdf at p 46.
72. C. Ineke Neutel, et al, Variation in Rates of Hospitalization for Excessive Vomiting in Pregnancy by Benedctin/Diclectin use in Canada, http://www.nvp-volumes.org/p1_9.htm at 2.
73. FDA and others have started to identify certain parts of this problem and the need for better understanding of the risks and better communication tools. For example, FDA recently announced the formation of an advisory committee to address certain product use and risk communication challenges and to help FDA craft more appropriate and understandable risk communications. It seems that this initiative will address more than field safety actions. See http://www.fda.gov/bbs/topics/NEWS/2007/NEW01648.html. One hope, of course, is that these initiatives be part of a coordinated, holistic assessment of field safety actions.
74. In its policy statement on postmarket surveillance, the HRS affirmatively declined to offer some "numerical" trigger for recalls or safety alerts. HRS recognized the difficulty in doing so given the variation among different situations and different patient and physician needs, available at http://www.hrsonline.org/Policy/CodingReimbursement/reimbursement/ physician/upload/HRSpercent20Devicepercent20Performancepercent20Guidelines.pdf at p. 4.
75. Someone can always sue the manufacturer on some claim of harm based on the failure to conduct a field safety action. There may well need to be some explicit preemption provision to avoid "second guessing" by plaintiffs, juries and courts of a decision not to conduct some field safety action or the type of field safety action. This does not need to include preemption of other causes of action based on the underlying issue. The author leaves those preemption issues to others.
76. The pressure on postmarket surveillance is coming from all fronts. Even the public media is involved. See, for example, Anna Wilde Mathews, Sequel for Vioxx Critic: Attack on Diabetes Pill, WALL STREET J (May 22, 2007) at A1.
77. Whether the perceived issues with Avandia are real or not seems an open question which the author leaves to the experts. Whether the media blitz and resulting decrease in use caused more harm than the purported issue is an open question. It is that risk assessment that is sorely lacking.