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Bias at the Gate?: The Pharmaceutical Industry's Influence on the Federally Approved Drug Compendia
Published online by Cambridge University Press: 06 January 2021
Extract
As of 2002, the Federal Food and Drug Administration (FDA) had approved Neurontin, a drug developed by the pharmaceutical company Pfizer, for two uses, the treatment of epilepsy and pain related to shingles. A staggering ninety-four percent of Neurontin prescriptions in the prior five years, however, were for other (non-FDA) approved uses. These other uses effectively tripled Medicaid’s costs for the drug between 1998 and 2003. Insurance companies covered the off-label uses because they appeared in the Drugdex compendium, a federally authorized listing of drugs that includes evidence regarding the drug’s effectiveness, clinical indications, and proper dosing. Drugdex included an additional forty-eight uses for Neurontin, ranging from bipolar disorder to the hiccups. Two other federally approved compendia existed at that time; one listed seven uses for Neurontin while the other listed only one.
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References
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6 Id. As discussed infra Part III, compendia may vary in the number of drug indications they include for a given listing.
7 Id.
8 Id.
9 Id.
10 Id.
11 Id.
12 Id.
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19 21 U.S.C. § 355(a) (2012).
20 Id. § 355(b)(1).
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58 Id.
59 Id. at 104-05.
60 Copeland, supra note 31, at 1042.
61 Id.
62 Eichel, supra note 22, at 409.
63 Kesselheim, supra note 14, at 228.
64 Id.
65 Id. The conditions for the dissemination of information on unapproved uses in journal articles include that:
the information is based on well-controlled clinical studies; the information is truthful and not misleading; the information is accompanied by [a] disclaimer, approved labeling, disclosure of known risks, and a bibliography of related publications; the journal is independent and adheres to standard peer review and editorial processes; the information is not accompanied by promotional materials; and the information is not distributed to consumers.
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66 Id.
67 31 U.S.C. § 3729(a)(1) (2012).
68 Id. § 3729(a)(2).
69 Id. § 3729(a).
70 Eichel, supra note 22, at 420.
71 Stone, supra note 47, at 57.
72 Id.
73 42 U.S.C. § 1396r-8(k)(6) (2006); Medicare Prescription Drug Benefit Manual: Chapter 6—Part D Drugs and Formulary Requirements, CTRS. FOR MEDICARE & MEDICAID SERVS. § 10.6, http://www.cms.gov/Medicare/Prescription-Drug-Coverage/PrescriptionDrugCovContra/downloads/Chapter6.pdf (last modified Feb. 19, 2010).
74 Stone, supra note 47, at 58.
75 Id.
76 Eichel, supra note 22, at 424 (quoting United States ex rel. Franklin v. Parke-Davis, 147 F. Supp. 2d 39, 51 (D. Mass. 2001)).
77 Stone, supra note 47, at 58.
78 MCKINNEY ET AL., supra note 4, at 3.
79 Id.
80 Id. at 14.
81 Pfister, supra note 17, at 584.
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85 Id.
86 MCKINNEY ET AL., supra note 4, at 3.
87 Id. at 5; Medicare Benefit Policy Manual: Chapter 15—Covered Medical and Other Health Services, CTRS. FOR MEDICARE & MEDICAID SERVS. § 50.4.5 (last revised May 10, 2013), http://www.cms.gov/Regulations-and-Guidance/Guidance/Manuals/Downloads/bp102c15.pdf.
88 Abelson & Pollack, supra note 84.
89 Id.
90 MCKINNEY ET AL. et al., supra note 4, at 27-28.
91 Id. at 28.
92 Id. at 3.
93 See, e.g., id. at 5; MEDCAC Meeting 3/30/2006—Compendia for Coverage of Off-Label Uses of Drugs and Biologics in an Anti-Cancer Chemotherapeutic Regimen, CTRS. FOR MEDICARE & MEDICAID SERVS., http://www.cms.gov/medicare-coverage-database/details/medcac-meeting-details.aspx?MEDCACId=33&fromdb=true (last visited Jan. 29, 2013).
94 MCKINNEY ET AL., supra note 4, at 4. The AHRQ published its final version of the Technology Assessment on May 7, 2007. AMY P. ABERNETHY ET AL., AHRQ, COMPENDIA FOR COVERAGE OF OFF-LABEL USES OF DRUGS AND BIOLOGICS IN AN ANTICANCER [SIC] CHEMOTHERAPEUTIC REGIMEN (2007), http://www.cms.gov/Medicare/Coverage/DeterminationProcess/downloads/id46TA.pdf.
95 Id.
96 Id.
97 Id.
98 Id.
99 Id.
100 MCKINNEY ET AL., supra note 4, at 1.
101 Id.
102 Id. at 5.
103 Abernethy el al., supra note 82, at 339 tbl.2.
104 See id. AHFS-DI seeks “to provide an evidence-based foundation for safe and effective drug therapy.” Id. Clinical Pharmacology's goal is “to provide [usable, concise] information on U.S. FDA-approved drugs, including prescription and nonprescription (OTC) pharmaceuticals.” Id. Drugdex states as its purpose, “to deliver unbiased drug information for those who prescribe, order, dispense, or administer medications.” Id. Finally, the NCCN compendia tries “to support decision making about the appropriate use of drug and biologic therapy in treating patients with cancer.” Id.
105 Id.
106 Id.
107 Id.
108 Id. at 339.
109 Id. at 340.
110 Id.
111 Id. “Despite documentation indicating that the compendia were last updated in 2008, they all cited literature from 2001 or earlier, except Drugdex, which included citations through 2007. Two compendia included conference abstracts from 1995 and 1996; [only Drugdex] updated its monograph with the citation of the published report.” Id. at 341.
112 MCKINNEY ET AL., supra note 4, at 6 (citing Thompson, D.F., Understanding Financial Conflicts of Interest, 329 NEW ENG. J. MED. 573-76 (1993)CrossRefGoogle ScholarPubMed).
113 Id.
114 Id. at 7.
115 Id. at 8.
116 Id.
117 Id. at 19.
118 Id. at 24-25.
119 Id. at 25.
120 Id.
121 Id.
122 See id. at 26.
123 Id.
124 Id. (citing Abernethy et al., supra note 82).
125 Id.
126 Id.
127 Id.
128 Id. at 26-27.
129 Id. at 27.
130 Id.
131 Id.
132 Id. at 29-34.
133 Id. at 29.
134 Id.
135 Twombly, Renee, Drug Compendia in Oncology: Are They Flawed? 101 J. NAT’L CANCER INST. 1604, 1605 (2009)CrossRefGoogle ScholarPubMed.
136 MCKINNEY ET AL., supra note 4, at 29.
137 Id. at 31.
138 Id. NCCN Drugs and Biologics Compendium breaks down the potential sources of conflicts of interest for every panel member on its website. Each reviewing panel, such as the Acute Myeloid Leukemia Panel or the Breast Cancer Risk Reduction Panel, is listed online, and each panel has links to its minutes and evidence, its panel attendance, and its panel disclosure. See NCCN Drugs and Biologics Compendium: Transparency: Process and Recommendations, NAT’L COMPREHENSIVE CANCER NETWORK, http://www.nccn.org/professionals/drug_compendium/content/changes.asp (last visited Jan. 29, 2013). Under panel disclosures, each panel member is listed along with whether he receives any financial support in the following four categories: (1) Clinical Research Report; (2) Advisory Boards, Speakers Bureau, Expert Witness, or Consultant; (3) Patent, Equity, or Royalty; or (4) Other. Id. If the panel member receives funds in one of those categories, the website lists the pharmaceutical company with whom the panel member is affiliated. See, e.g., About NCCN: Acute Myeloid Leukemia Panel, NAT’L COMPREHENSIVE CANCER NETWORK, http://www.nccn.org/disclosures/panel_list.asp?ID=39&MeetingDate=3/28/2012 (last updated Mar. 28, 2012).
139 MCKINNEY ET AL., supra note 4, at 31.
140 Id. at 32.
141 Id.
142 See id.; NCCN Guidelines & Clinical Resources: Disclosure of NCCN Organizational Relationships, NAT’L COMPREHENSIVE CANCER NETWORK, http://www.nccn.org/about/financial_support.asp (last visited Jan. 29, 2013).
143 MCKINNEY ET AL., supra note 4, at 32; NCCN Guidelines & Clinical Resources: Disclosure, supra note 142.
144 MCKINNEY ET AL., supra note 4, at 29.
145 Id.
146 Id.
147 Id. at 29-30.
148 Id. at 30.
149 See id. at 30-31; David Armstrong, Cosy [sic] World of Cancer-Drug Compendia Draws Questions, WALL ST. J. (Jan. 27, 2009, 5:38 PM), http://blogs.wsj.com/health/2009/01/27/cosy-world-of-cancer-drug-compendia-draws-questions/.
150 MCKINNEY ET AL., supra note 4, at 30; see also Armstrong, supra note 149.
151 MCKINNEY ET AL., supra note 4, at 30.
152 Armstrong, supra note 149.
153 Id.
154 Id.
155 See id.; Twombly, supra note 135, at 1605.
156 Twombly, supra note 135, at 1605.
157 Id.; see also MCKINNEY ET AL., supra note 4, at 33.
158 MCKINNEY ET AL., supra note 4, at 33.
159 Id.
160 Id.
161 Id. at 33-34.
162 Id.
163 Id.
164 Twombly, supra note 135, at 1605.
165 See MCKINNEY ET AL., supra note 4, at 38.
166 Abernethy et al., supra note 82, at 340.
167 MCKINNEY ET AL., supra note 4, at 39.
168 Id.
169 Id. at 21.
170 Id.
171 Id. at 23.
172 Id.
173 Id.
174 Id.
175 See generally Vedula, S. Swaroop et al., Outcome Reporting in Industry-Sponsored Trials of Gabapentin for Off-Label Use, 361 NEW ENG. J. MED. 1963 (2009)CrossRefGoogle ScholarPubMed.
176 Id. at 1964.
177 Id.
178 Id. at 1965.
179 Clinicaltrials.gov Protocol Data Element Definitions (Draft), CLINICALTRIALS.GOV (Jan. 2013), http://prsinfo.clinicaltrials.gov/definitions.html.
180 Vedula et al., supra note 175, at 1966.
181 Id.
182 Id.
183 Id. at 1969.
184 Id.
185 Id.
186 Id.
187 S. Swaroop Vedula et al., Implementation of a Publication Strategy in the Context of Reporting Biases. A Case Study Based on New Documents from Neurontin Litigation, TRIALS 2 (Aug. 13, 2012), http://www.trialsjournal.com/content/pdf/1745-6215-13-136.pdf.
188 Id. at 2.
189 Id.
190 Id. at 4-9.
191 Id. at 4.
192 Id.
193 Id.
194 Id. at 5.
195 Id. The authors define spin as:
[E]mphasis in the published report on outcomes that were not specified in the study protocol (Study 879-201); conclusions that did not match study findings described in the internal company research report (Study 945-220); extensive rationale to explain away statistically non-significant (unfavorable to the sponsor) findings (Study 945-209); [n]o study number – Gorson; conclusion of treatment effectiveness from an uncontrolled study (Study 945-250); emphasis on statistically significant secondary outcomes despite negative findings for the primary outcome (Study 945-271); and an explicit description of an attempt to spin study findings (as described in internal company emails) (Study 945-306).
Id. at 5-6.
196 Id. at 6.
197 Id.
198 Id. at 7.
199 Id. at 7-9.
200 Id. at 7.
201 Id.
202 Id. An email communication by a Senior Marketing Manager stated, “[F]rom a MKT point of view we are not interested at all in having this paper published because it is negative!!! So don't put this as a high priority in your list … .” Id. (citation omitted).
203 Id. at 9.
204 Id. at 10.
205 Id. at 11.
206 Id.
207 Alexander Gaffney, Senate Investigation Claims Medtronic Edited, Influenced Studies, REGULATORY FOCUS (Oct. 24, 2012), http://www.raps.org/focus-online/news/news-article-view/article/2465/senate-investigation-claims-medtronic-edited-influenced-studies.aspx.
208 Id.
209 Id.
210 Id.
211 Id.
212 Seife, Charles, Is Drug Research Trustworthy?, 307 SCI. AM. 56, 57 (2012)CrossRefGoogle ScholarPubMed.
213 Mitka, Mike, Off-Label Cancer Drug Compendia Found Outdated and Incomplete, 301 JAMA 1645, 1646 (2009)CrossRefGoogle ScholarPubMed.
214 Id.
215 Justice Department Recovers Nearly $5 Billion in False Claims Act Cases in Fiscal Year 2012, U.S. DEP't OF JUSTICE (Dec. 4, 2012), http://www.justice.gov/opa/pr/2012/December/12-ag-1439.html.
216 Andrew Pollack & Mosi Secret, Amgen Agrees to Pay $762 Million for Marketing Anemia Drug for Off-Label Use, N.Y. TIMES (Dec. 18, 2012), http://www.nytimes.com/2012/12/19/business/amgen-agrees-to-pay-762-million-in-drug-case.html.
217 Id.
218 Id.
219 Craft, supra note 52, at 124.
220 Bryan Cote, Oncology Compendia: Greater Transparency and Regulatory Attention at the Forefront, ONCOLOGY BUS. REV. 10, 12 (Nov. 2008), http://www.oncbiz.com/documents/OBR_nov08_OC.pdf.
221 Id. at 12.
222 Id.
223 Id. at 12-14.
224 Id. at 14.
225 Vedula et al., supra note 175, at 1970.
226 MCKINNEY ET AL., supra note 4, at 23.
227 Vedula et al., supra note 175, at 1970.
228 MCKINNEY ET AL., supra note 4, at 71 tbl.2.
229 Id. at 55.
230 Twombly, supra note 135, at 1605.
231 MCKINNEY ET AL., supra note 4, at 47-48.
232 Id. at 48.
233 Id. at 49.
234 Id.
235 Id. at 50.
236 Id. at 51.
237 Id. at 52.
238 Id.
239 Id.
240 Id. at 53.
241 Id. at 54.
242 See Vedula et al., supra note 187, at 6-9.
243 United States’ Statement of Interest in Opposition to Defendant Parke-Davis’ Motion for Summary Judgment at 3, United States ex rel. Franklin v. Pfizer, No. 96-11651-PBS (D. Mass., May 23, 2003); see also Amended Complaint and Demand for Jury Trial at para. 66, United States ex rel. Provuncher v. Angioscore, No. 09-12176-RGS (D. Mass. Aug. 12, 2011).
244 While possible that inclusions for a use in multiple compendia resulted from a particularly aggressive or persistent fraudulent marketing scheme, it is more likely that the inclusion is valid because it underwent the review process in different compendia. In theory, where one compendium's conflicts of interest policy or review guidelines have a gap, another compendium's policy should compensate.