Personalized medicine and rescuing "unsafe" drugs with pharmacogenomics: A regulatory perspective

Food and Drug Law Journal

Volumn 65, Issue 1, 2010, Pages

  Avery, Matthew ^a  

^a Baker Botts LLP   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BIOLOGICAL MARKER;

CONSUMER; DEVICE; DIAGNOSTIC TEST; DRUG CONTROL; DRUG INDUSTRY; DRUG LABELING; DRUG SAFETY; FOOD AND DRUG ADMINISTRATION; GENETIC ANALYSIS; HUMAN; LABORATORY TEST; PHARMACOGENOMICS; REVIEW; VALIDATION STUDY;

CLINICAL LABORATORY TECHNIQUES; DIAGNOSIS; DRUG APPROVAL; HUMANS; INDIVIDUALIZED MEDICINE; LEGISLATION, DRUG; ORPHAN DRUG PRODUCTION; PHARMACOGENETICS; UNITED STATES; UNITED STATES FOOD AND DRUG ADMINISTRATION;

EID: 77949646743     PISSN: 1064590X     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Review

References (376)

1. Press Release, Senator Barack Obama, Obama Introduces Bill to Help Tap Power of Genomics to Find Cures (Aug. 9, 2006) (statements in support of the Genomics and Personalized Medicine Act) (internal introductory tags and quotation marks omitted), available at http://obama.senate.gov/press/ 060809-obama-introduce-9/index.php.
2. See FDA. INNOVATION OR STAGNATION?: CHALLENGE AND OPPORTUNITY ON THE CRITICAL PATH TO NEW MEDICAL PRODUCTS, at i (2004) [hereinafter FDA, INNOVATION OR STAGNATION]; Friend, Tim, Genome Projects Complete Sequence; Unraveling of DNA Code is a Blueprint for the Future of Medicine, USA TODAY (June 23, 2000) at A1.
3. DEP'T OF HEALTH & HUMAN SERVICES, SECRETARY'S ADVISORY COMM. ON GENETICS, HEALTH & SOC'Y, REALIZING THE POTENTIAL OF PHARMACOGENOMICS 1 (2008) [hereinafter SACGHS PHARMACOGENOMICS REPORT]; Roses, Allen D., Pharmacogenetics and the Practice of Medicine, 405 NATURE 857, 857 (2000).
4. See Binzak, Barbara Ann, How Pharmacogenomics Will Impact the Federal Regulation of Clinical Trials and the New Drug Approval Process, 58 FOOD & DRUG L.J. 103, 103 (2003);
5. SACGHS PHARMACOGENOMICS REPORT, supra note 3, at 1-2. While the term "personalized medicine" is sometimes broadly defined as tailoring a medical treatment based on a patients susceptibility to a disease or response to a specific treatment, this article uses the term more narrowly to refer to the tailoring of a medical treatment based on a patients genotype.
6. See Woodcock, Janet, FDA Policy on Pharmacogenomic Data in Drug Development, 66 LA. L. REV. 91, 98-99 (2005).
7. See Lesko, Lawrence J. et al., Pharmacogenetics and Pharmacogenomics in Drug Development and Regulatory Decision Making, 43 J. CLINICAL PHARMACOLOGY 342, 351 (2003).
8. Dunn, Kathleen, Personalized Medicines: Implications for Pharma, PHARM. EXEC. (Dec. 1, 2009).
9. See FDA, Table of Valid Genomic Biomarkers in the Context of Approved Drug Labels (Sept. 10, 2008) [hereinafter FDA, Table of Valid Genomic Biomarkers 2008], http://www.fda.gov/cder/genomics/genomic-biomarkers-table.htm (last visited Mar. 11, 2009);
10. SACGHS PHARMACOGENOMICS REPORT, supra note 3, at 1.
11. See FDA, INNOVATION OR STAGNATION, supra note 2, at i.
12. BURRILL & CO., BIOTECH 2008 LIFE SCIENCES: A 20/20 VISION TO 2030, at 43 (2008).
13. In 2009, FDA approved seventeen new molecular entities (NMEs) and seven biological license applications (BLAs). Arnold, Matthew, FDA BLA Approvals Rose in 2009 While NMEs Stumbled, MED. MARKETING & MEDIA, (Dec. 31,2009), http://www.mmm-online.com/fda-bla-approvals- rose-in-2009-while-nmes-stumbled/article/160496/.
14. Interestingly, the number of applications filed to investigate new drugs (INDs) has varied little since 1996, with approximately 1700 INDs filed per year. FDA, Number of INDs Received: Calendar Years 1986-2006. http://www.fda.gov/cder/rdmt/Cyindrec.htm.
15. However, over the same period, the number of applications filed to market new molecular entities and biologies (i.e., NDAs and BLAs for NMEs) dropped almost 50 percent. FDA, INNOVATION OR STAGNATION, supra note 2, at 2 fig.2.
16. Hughes, Bethan, 2007 FDA Drug Approvals: A Year of Flux, 7 NATURE REV. DRUG DISCOVERY 107, 107 (2008);
17. see also PETER BARTON HUTT ET AL., FOOD AND DRUG LAW: CASES AND MATERIALS 714 (3d ed. 2007). In the past decade, the pharmaceutical industry has found that FDA is "requesting more nonclinical studies and more clinical trials, of longer duration, with more subjects, containing more arms for additional dosage levels, with more diverse subjects, and longer follow up. The result [is] a significant reduction in NDAs submitted to the agency and an approximate doubling of the average cost of an NDA." Id.
18. FDA, INNOVATION OR STAGNATION, supra note 2, at 3.
19. See DiMasi, Joseph A. & Grabowski, Henry G., The Cost of Biopharmaceutical R&D: Is Biotech Different?, 28 MANAGERIAL & DECISION ECON. 469, 477 (2007).
20. FDA, INNOVATION OR STAGNATION, supra note 2, at i.
21. See Binzak, supra note 4, at 104; FDA, INNOVATION OR STAGNATION, supra note 2. at ii.
22. TUFTS CENTER FOR THE STUDY OF DRUG DEVELOPMENT, IMPACT REPORT 2009: LARGE PHARMA SUCCESS RATE FOR DRUGS ENTERING CLINICAL TRIALS IN 1993-04: 16% (K.I. Kaitin ed., 2009);
23. HUTT ET AL., supra note 12, at 624.
24. Lesko, Lawrence J. & Woodcock. Janet, Translation of Pharmacogenomics and Pharmacogenetics: A Regulatory Perspective, 3 NATURE REV. DRUG DISCOVERY 763, 764 (2004);
25. HUTT ET AL., supra note 12, at 624. In addition to safety and efficacy, a drug candidate might fail to make it to market because of commercialization issues. Lesko & Wookcock, supra. Note that this article uses "efficacy" and "effectiveness" interchangeably, though the author acknowledges that "effectiveness" is the preferred term of art. Interview with Peter Barton Hutt, Senior Counsel, Covington & Burling LLP, in Wash., DC. (Feb. 13, 2009);
26. see also SACGHS PHARMACOGENOMICS REPORT, supra note 3, at 34 n.234 ("[T]he term 'effectiveness' is used as a measure of how well the test performs in 'real-world' clinical settings, and 'efficacy' is used for outcomes seen in controlled research settings.").
27. See BOSTON CONSULTING GROUP, A REVOLUTION IN R&D: HOW GENOMICS AND GENETICS ARE TRANSFORMING THE BIOPHARMACEUTICAL INDUSTRY, at 12 (2001) (estimating that drug companies could rescue two new drugs per year using PGx technology), available at http://www.bcg.com/publications/ files/eng-genomic-sgenetics-rep-11-01.pdf. For the sake of simplicity, this paper will categorize patients into three categories: "Positive responders," or simply "responders," are those patients who have an efficacious response to the drug. "Non-responders" are those patients for whom the drug fails to demonstrate any benefit. Finally, "adverse responders" are those patients who suffer severe adverse reactions from taking the drug.
28. See Crews, Margaret, Comment, Pharmacogenomics: Tailoring the Drug Approval Process for Designer Drugs, 24 J. CONTEMP. HEALTH L. & POL'Y 363, 364 (2008).
29. Woodcock, supra note 5, at 95.
30. It is beyond the scope of this article to analyze the following issues related to pharmacogenomics and personalized medicine: 1) cross-labeling issues where a third party device manufacturer independently develops a pharmacogenomic diagnostic device to be used in combination with a sponsor's approved drug; 2) the use of pharmacogenomic data in postmarketing studies; 3) ethical issues related to stratifying patient populations by race, ethnicity, genetics or other factors; 4) the use of genetic data in predicting disease susceptibility. For a discussion of cross-labeling issues, see generally Sasjack, Scott, Demanding Individually Safe Drugs Today: Overcoming the Cross-labeling Legal Hurdle to Pharmacogenomics, 34 AM. J. L. MED. 7 (2008).
31. For a discussion of race-based medicine, compare Cohn, Jay N., The Use of Race and Ethnicity in Medicine: Lessons from the African-American Heart Failure Trial, 34 J.L. MED. & ETHICS 552 (2006)
32. and Hoffman, Sharon, "Racially-Tailored" Medicine Unraveled, 55 AM. U.L. REV. 395 (2005).
33. For a discussion of using genetic information to predict disease susceptibility, see generally Roses, supra note 3, at 863-865 and Wade, Nicholas, Genes Show Limited Value in Predicting Diseases, N.Y. TIMES, (Apr. 16, 2009).
34. See Lesko, L.J., Personalized Medicine: Elusive Dream or Imminent Reality?, 81 CLINICAL PHARMACOLOGY & THERAPEUTICS 807, 809 (2007);
35. see also, Dep't of Energy, Office of Sci., Human Genome Program, Pharmacogenomics, http://www/ornl.gov/sci/techresources/Human-Genome/medi-cine/ pharma.shtml.
36. Lesko, supra note 23, at 809.
37. See Grant, Denis M., Pharmacogenomics and the Changing Face of Clinical Pharmacology, 6 CAN. J. CLINICAL PHARMACOLOGY 131, 131 (1999);
38. Lesko, supra note 23, at 809.
39. Lesko, supra note 23, at 809.
40. Lesko, L.J. & Woodcock, J., Pharmacogenomic-Guided Drug Development: Regulatory Perspective, 2 PHARMACOGENOMICS J. 20, 20-21 (2002);
41. Roses, supra note 3, at 858. Pharmacogenetics is a scientific subset of pharmacogenomics that studies how genetic variations in individuals and populations result in different systemic drug exposure patterns to drug doses and dosing regimens. Lesko & Woodcock, supra, at 21;
42. Roses, supra note 3, at 858. Similarly, toxicogenomics is a subset of pharmacogenomics that applies genomic concepts to the study of drug toxicity. Lesko et al., supra note 6, at 346. References in this article to pharmacogenomics are intended to include pharmacogenetics, toxicogenomics, and similar sub-disciplines.
43. SACGHS PHARMACOGENOMICS REPORT, supra note 3, at 9. Of course, variations may occur because of other intrinsic factors, such as the individual's age, race, or sex. Variability can also be attributed to extrinsic factors, such as the individual's diet, consumption of alcohol or tobacco, or concurrent use of other drug therapies. Huang, S.-M. & Temple, R., Is This the Drug or Dose for You?: Impact and Consideration of Ethnic Factors in Global Drug Development, Regulatory Review, and Clinical Practice, 84 CLINICAL PHARMACOLOGY & THERAPEUTICS 287, 287 (2008).
44. See THE ROYAL SOCIETY, PERSONALISED MEDICINES: HOPES AND REALITIES (2005), available at http://royalsociety.org/displaypagedoc.asp?id=15874.
45. See, e.g., Agarwal, Amit, Overlooked Opportunities, PHARM. EXEC. (Jan. 1, 2009) (discussing the typical trial-and-error treatment of multiple sclerosis).
46. See Spear, B.B. et al., Clinical Application of Pharmacogenetics, 7 TRENDS MOLECULAR. MED. 201 (2001). For example, treatments for osteoporosis, arthritis, and migraines fail to show effect almost 50 percent of the time. See Agarwal, supra note 30;
47. see also Khan, Arif et al., Are Placebo Controls Necessary to Test New Antidepressants and Anxiolytics?, 5 INT'L J. NEUROPSYCHOPHARMACOLOGY 193, 195-196 (2002));
48. see also Roses, Allen D., Pharmacogenetics and Drug Development: The Path to Safer and More Effective Drugs, 5 NATURE REVS. GENETICS 645, 648 (2004) (stating that many drugs are approved with as little as 30 percent efficacy among the general patient population).
49. See Garrison, L.P., Jr. & Austin, M.J., Linking Pharmacogenetics-based Diagnostics and Drugs for Personalized Medicine, 25 HEALTH AFFAIRS 1281 (2006).
50. Pollack, Andrew, Patient's DNA May Be Signal to Tailor Medication, NY TIMES, (Dec. 30, 2008);
51. Goldstein, Jacob, The Next Step in Cancer Drugs: Who Should NOT Get Them, WALL ST. J. HEALTH BLOG (Jan. 14, 2009), http://blogs.wsj.com/health/2009/01/14/the-next-step-in-cancer-drugs-who- should-notget-them/;
52. see also Roses, supra note 3, at 863.
53. Xie, Hong-Guang & Frueh, Felix W, Pharmacogenomics Steps Toward Personalized Medicine, 2 PERSONALIZED MED. 325, 325-326 (2005);
54. Lesko, supra note 23, at 808.
55. Lesko, supra note 23, at 808.
56. Id.
57. Roses, supra note 3, at 862;
58. Lesko, supra note 23, at 808.
59. Woodcock, supra note 5, at 91.
60. Id. at 93.
61. Id. at 91.
62. Id.
63. See id. at 92. For example, a drug candidate that is safe and effective in 99 percent of the population may fail to receive FDA approval because the remaining 1 percent experiences a potentially fatal side effect.
64. See id.
65. Sasjack, supra note 22, at 9;
66. see also Roses, supra note 3, at 863.
67. See FDA, Table of Valid Genomic Biomarkers 2008, supra note 8:
68. Lesko & Woodcock, supra note 27, at 20.
69. Lesko & Woodcock, supra note 27, at 20. Considering the current political focus on healthcare reform, an arguably more important result is that personalized medicine would allow physicians to lower overall healthcare costs by avoiding wasteful prescriptions to non-responders and adverse responders. See id. at 21.
70. FDA has only approved four drugs with labeling that require a physician to administer a genetic test prior to prescribing the drug. See FDA, Table of Valid Genomic Biomarkers 2008, supra note 8. They are Herceptin (trastuzumab), Selzentry (maraviroc), Erbitux (cetuximab), and Sprycel (dasatinib). Id.
71. Xie & Frueh, supra note 34, at 329;
72. Lesko & Woodcock, supra note 27, at 23.
73. Harries, M. & Smith, I., The Development and Clinical Use of trastuzumab (Herceptin), 9 ENDOCRINE-RELATED CANCER 75, 78-79 (2002);
74. Xie & Frueh, supra note 34, at 329.
75. SACGHS PHARMACOGENOMICS REPORT, supra note 3, at 26.
76. Id.
77. Id.
78. See Roses, supra note 31, at 648.
79. GENENTECH, HERCEPTIN FINAL DRAFT LABEL, U.S. BLA SUPPLEMENT, available at http://www.fda.gov/cder/foi/label/2002/trasgen082802LB.pdf;
80. Lesko & Woodcock, supra note 27, at 23.
81. Lesko & Woodcock, supra note 27, at 23.
82. This is a significant savings, since Herceptin costs approximately $40,000 to $60,000 per patient per year. See Neyt, M. et al., An Economic Evaluation of Herceptin in Adjuvant Setting, 17 ANN. ONCOLOGY 381 (2006).
83. Lesko & Woodcock, supra note 27, at 23.
84. Introgen Advexin Clinical Biomaker Data Demonstrate Recurrent Head and Neck Cancer Patients Likely to Have a Survival Benefit From Advexin, REUTERS (Jan. 22, 2007) ("Tumor disease control was observed in 75 percent of patients with the abnormal p53 biomarker compared to 18% of patients without the p53 biomarker."), http://www.reuters.com/article/ idUSIN20070122134705INGN20070122.
85. E-mail from Peter Barton Hutt, Senior Counsel, Covington & Burling LLP, to author (Feb. 23, 2009, 13:42:08 PST) (on file with author).
86. Young, Donna, Introgen Takes a Hit on FDA's Refusal to Review Gene Therapy, BIOWORLD TODAY (Sept. 3, 2008).
87. E-mail from Peter Barton Hutt, supra note 59.
88. Introgen Files for Bankruptcy, Sees Exit in 2009, REUTERS (Dec. 3, 2006), http://www.reuters.com/article/idUSN0343564920081203.
89. Reeder, C.E. & Dickson, W. Michael, Economic Implications of Pharmacogenomics, in PHARMACOGENOMICS: SOCIAL, ETHICAL AND CLINICAL DIMENSIONS 229. 232 (Mark. A. Rothstein ed., 2003).
90. But see Keeling, Peter & Roth, Mollie, Getting Personal(ized), PHARM. EXEC. (Oct. 1, 2008) (arguing that a sponsor can actually increase sales by coupling its drug with a companion diagnostic test because "prescribers are more likely to use a drug that comes with a test - at a rate of 70-90 percent more than other more traditional drugs - because the test provides greater evidence of likely positive patient outcome"). Furthermore, if PGx data is only used to exclude a small group of likely adverse responders, it may be a substantially more attractive investment.
91. Evans. Barbara J. et al., Creating Incentives for Genomic Research to Improve Targeting of Therapies, 10 NATURE MED. 1289, 1289 (2004).
92. See SACGHS PHARMACOGENOMICS REPORT, supra note 3, at 2. Also note that the incentive to develop and use pharmacogenomic-based diagnostic tests is further impeded by the refusal of most health insurers to cover the cost of such tests. In fact, Medicare is statutorily prohibited from reimbursing the costs of most PGx tests. Id. at 3, 60. It is also interesting to note that the cost of a PGx test is easier to justify for more expensive therapies. Id. at 25;
93. Flowers, CR. & Veenstra, D., The Role of Cost-Effectiveness Analysis in the Era of Pharmacogenomics, 22 PHARMACOECONOMICS 481 (2004). It is, however, beyond the scope of this article to explore the problems associated with third-party payers.
94. Spice, Byron, Pharmacogenomics: One Day, it May Allow Doctors to Tailor Drugs to Individuals, PITTSBURGH POST-GAZETTE (July 9,2000), at AO, available at http://www.post-gazette.com/ healthscience/20000709pharmacogenomics.asp;
95. see also Keeling & Roth, supra note 63.
96. See Evans et al., supra note 64, at 759.
97. See SACGHS PHARMACOGENOMICS REPORT, supra note 3, at 22.
98. See NUFFIELD COUNCIL ON BIOETHICS, PHARMACOGENETICS: ETHICAL ISSUES (2003), available at http://www.nuffieldbioethics.org/fileLibrary/pdf/pharmacogenetics- report.pdf;
99. SACGHS PHARMACOGENOMICS REPORT, supra note 3, at 22;
100. Roses, supra note 3, at 862.
101. But see Emilien, G. et al., Impact of Genomics on Drug Discovery and Clinical Medicine, 93 Q. J. MED. 391, 394 (2000) (arguing that clinical trials that include PGx testing may be more efficient because they will improve the use of inclusion and exclusion criteria for the trial);
102. Bonnie, A. et al., Clinical Trials in the Genomic Era: Effects of Protective Genotypes on Sample Size and Duration of Trial, 21 CONTROLLED CLIN. TRIALS 7 (2000) (same);
103. BOSTON CONSULTING GROUP, supra note 19 (estimating that genomic technology could save drug companies an average of $300 million as a result of increased efficiency).
104. See, e.g., Agarwal, supra note 30.
105. See Pritchard, J.F. et al., Making Better Drugs: Decision Gates in Non-Clinical Drug Development, 2 NATURE REV. DRUG DISCOVERY 542, 542 (2003) (describing failure risks associated with drug discovery).
106. See supra text accompanying note 14.
107. Lesko & Woodcock, supra note 18, at 764.
108. Lesko. supra note 23, at 810.
109. See id.;
110. Lesko & Woodcock, supra note 27, at 21.
111. Reeder & Dickson, supra note 63, at 231-232.
112. See Evans et al., supra note 64, at 758-759.
113. See Li, Gen. Site Activation: The Key to More Efficient Clinical Trials. PHARM. EXEC. (Dec. 12, 2008) (reporting that single clinical trial can involve up to 50,000 patients, last five years or longer, and cost up to $500 million).
114. See Woodcock, supra note 5. at 93.
115. In fact, as a matter of practice, a sponsor will almost always abandon a drug in the middle of clinical trials if it only demonstrates efficacy in a small subgroup. See Roses, supra note 31, at 648.
116. The motive to use PGx to rescue a failing drug may be greater where no alternative treatment exists for the target disease state. See NUFFIELD COUNCIL ON BIOETHICS, supra note 69.
117. See, e.g., 21 U.S.C. §355(a) ("No person shall introduce or deliver for introduction into interstate commerce any new drug, unless an approval of an application ... is effective with respect to such drug.").
118. See 21 U.S.C. §355(d).
119. 21 C.F.R. §312.23.
120. FDA, CENTER FOR DRUG EVALUATION AND RESEARCH (CDER), THE CDER HANDBOOK 7 (1998) [hereinafter FDA, CDER HANDBOOK], available at http://www.fda.gov/cder/handbook/handbook.pdf.
121. During pre-clinical testing, the sponsor must obtain toxicological and pharmacological information on the drugs. See 21 C.F.R. 312.23(a)(8);
122. FDA, CDER HANDBOOK, supra note 85, at 5.
123. In practice, however, most investigational new drug (IND) applicants only submit toxicology data. Interview with Peter Barton Hutt, supra note 18. While FDA does not directly regulate preclinical testing, the agency indirectly regulates how preclinical testing is conducted because it uses the results of these tests to determine whether to allow human clinical trials.
124. Consequently, as part of preclinical testing, the sponsor must develop a "pharmacological profile" of the new drug to allow FDA to determine whether "it is reasonably safe to proceed with human trials of the drug." FDA, CDER HANDBOOK, supra note 85, at 5, 7.
125. See 21 U.S.C. §355(d);
126. C.F.R. §312.23.
127. Alternatively, the IND process can begin with exploratory IND studies (so-called "Phase Zero" studies), which involve administering the drug to a very limited number of healthy human volunteers for a limited duration (e.g., one week). Phase Zero studies are optional, and generally used to gather preliminary pharmacokinetic and pharmacodynamics data on multiple drug candidates to identify the best compound(s) to advance to full-scale clinical trials. Draft Guidance for Industry. Investigators, and Reviewers: Exploratory IND Studies, 70 Fed. Reg. 19,764 (Apr. 14, 2005).
128. FDA, CDER HANDBOOK, supra note 85. Phase I studies are sometimes divided into Phase IA and Phase IB, where Phase IA tests the drug in healthy volunteers and Phase IB tests the drug in patients with the disease.
129. See 21 C FR. §312.21(a) (stating that Phase I studies are "designed to determine the metabolism and pharmacologic actions of the drug in humans, the side effects associated with increasing doses, and, if possible, to gain early evidence on effectiveness. ... Phase I studies also include studies of drug metabolism, structure-activity relationships, and mechanism of action in humans, as well as studies in which investigational drugs are used as research tools to explore biological phenomena or disease processes);
130. HUTT ET AL., supra note 12, at 630.
131. FDA, CDER HANDBOOK, supra note 85, at 8.
132. Id.
133. Id.: see also 21 C.F.R. §312.21(b). Phase II studies are sometimes divided into Phase IIA and Phase HB. Phase HA is designed to assess dosing requirements and Phase HB is designed to study efficacy.
134. PDA, CDER HANDBOOK, supra note 85. at 8.
135. Id; see also 21 C.F.R. §312.21(c).
136. See Li, supra note 78, CDER HANDBOOK, supra note 85. at 9.
137. Huang, S.-M. & Temple, R., Is This the Drug or Dose for You?: Impact and Consideration of Ethnic Factors in Global Drug Development, Regulatory Review, and Clinical Practice, 84 CLINICAL PHARMACOLOGY THERAPEUTICS 287,288 (2008);
138. see also 21 C.F.R. §314.126. Placebo-controlled means that there is also a patient population that randomly receives a placebo, which serves as a control against which safety and efficacy in the active group can be determined. Double-blind means that neither the physicians nor the patients know who is receiving placebos - only the researchers overseeing the study know which patients are receiving actual treatment.
139. Huang & Temple, supra note 97, at 288.
140. See 21 C.F.R. § 314.50;
141. Huang & Temple, supra note 97, at 288.
142. Huang & Temple, supra note 97, at 288 ("What this means is that we have reasonably good data on group safety and effectiveness dose-response relationships but cannot determine whether individuals differ in important ways in their responses ... . If such differences were predicted by a demographic feature, they might be detected by standard subset analyses, but if they reflect unrecognized genetic or physiologic pharmacodynamic (PD) differences, they would not.").
143. This article refers to NDAs. Developers of biological products file Biologicals License Applications (BLAs) rather than NDAs. For purposes of this article, any discussion of NDAs is also applicable to BLAs.
144. Landen, Pennington Parker, Federal Preemption and the Drug Industry: Can Courts Co-Regulate?. 43 FOOD DRUG COSM. L.J. 85, 100 (1988);
145. see also 21 U.S.C. § 355(a)-(b). In general, the NDA should contain reports on the following: 1) chemistry, manufacturing, and control; 2) nonclinical pharmacology and toxicology; 3) human pharmacokinetics and bioavailability; 4) clinical efficacy and safety data (both generally and by sex, age and race).
146. See 21 C.F.R. § 314.50;
147. see also FDA, CDER HANDBOOK, supra note 85, at 21.
148. See 21 U.S.C. §355(d). After reviewing the application, FDA may take one of three actions: 1) send a "not approvable" letter stating that the drug cannot be approved; 2) send an "approvable" letter indicating that the drug could be approved if certain changes are made; or 3) send an "approval" letter stating that the drug is approved as it stands.
149. See FDA, CDER HANDBOOK, supra note 85, at 24;
150. see also 21 C.F.R. §§ 314.105, 314.110, 314.120.
151. See 21 U.S.C. § 355(a).
152. See 21 U.S.C. §§ 32l(m), 352(f)(1)-(2);
153. Merrill, Richard A., Compensation for Prescription Drug Injuries, 59 VA. L. REV. 1 (1973).
154. 21 U.S.C. § 355(b)(1)(F), (d)(7).
155. See Lesko et al., supra note 6, at 351.
156. See SACGHS PHARMACOGENOMICS REPORT, supra note 3, at 25.
157. Id. at 10.
158. Id. at 25.
159. Id.
160. Id.
161. See 21 U.S.C. §360c(a)(1);
162. SACGHS PHARMACOGENOMICS REPORT, supra note 3, at 52;
163. Gibbs, Jeffrey N., Personalized Medicine: Panacea or Pipedream?, FDLI UPDATE (Sept./Oct. 2008), at 6, 8.
164. SACGHS PHARMACOGENOMICS REPORT, supra note 3, at 52.
165. See FDA, Device Classes, http://www.fda.gov/CDRH/DEVADVICE/3132. html; 21 U.S.C. §§ 351, 352, 360, 360f, 360h, 360i, 360j;
166. see also 21 C.F.R. §§ 801, 809, 820.
167. Note that general controls require submission of a 510(k) premarket notification for both Class I and II devices. See 21 U.S.C. §§ 360(k), 360c(i). However, by regulation, almost all Class I and many Class II devices are exempt from the 510(k) submission requirement.
168. See 21 C.F.R. §§ 862-892; FDA, Class I/II Exemptions, http://www.fda.gov/CDRH/DEVADVICE/3133.html.
169. See 21 U.S.C. §§ 360(k), 360c(i).
170. See FDA PREMARKET NOTIFICATION 510(K). http://www.fda.gov/CDRH/DEVADVICE/314.html;
171. SACGHS PHARMACOGENOMICS REPORT, supra note 3, at 52.
172. See 21 U.S.C. § 360c(a)(1)(B).
173. See id. §360c(a)(1)(C)(ii);
174. SACGHS PHARMACOGENOMICS REPORT, supra note 3, at 52. Note that devices with no equivalent predicate are classified as Class III devices by default, regardless of their safety. Consequently, sponsors of these devices can request a down-classification to either a Class I or II device if they can show the device presents only a low or moderate risk. Id. If FDA approves the down-classification, the device can be marketed without obtaining a PMA.
175. See FDA, CENTER FOR DEVICES & RADIOLOGICAL HEALTH (CDRH), NEW SECTION 513(F)(2) - EVALUATION OF AUTOMATIC CLASS III DESIGNATION, GUIDANCE FOR INDUSTRY AND CDRH STAFF (1998), available at http://www.fda.gov/cdrh/modact/ clasiii.pdf.
176. See 21 U.S.C. §360c(a)(1)(C);
177. SACGHS PHARMACOGENOMICS REPORT, supra note 3, at 52. However, sponsors of Class III devices with no equivalent predicate device can request a down-classification to either a Class I or II device if the device is of low or moderate risk. See 21 U.S.C. §360c(f)(3). If FDA approves the down-classification, the device can be marketed without obtaining a PMA.
178. See FDA, Supra note 120.
179. 21 U.S.C. § 360e.
180. FDA, INTERCENTER AGREEMENT BETWEEN THE CENTER FOR DRUG EVALUATION AND RESEARCH (CDER) AND THE CENTER FOR DEVICES AND RADIOLOGICAL HEALTH (CDRH), at VII.A.1(a)ii., VII.B (2006), available at http://www.fda.gov/oc/ombudsman/drug-dev.htm.
181. SACGHS PHARMACOGENOMICS REPORT, supra note 3, at 51.
182. See Medical Device Amendments of 1976, Pub. L. No. 94-295, 90 Stat. 539 (May 28, 1976) (codified as amended in scattered sections of 21 U.S.C);
183. Safe Medical Devices Act of 1990, Pub. L. No. 101-629, §16, 104 Stat. 4511 (codified at 21 U.S.C. §353(g)).
184. SACGHS PHARMACOGENOMICS REPORT, supra note 3, at 53-54.
185. See Clinical Laboratory Improvements Amendments of 1988, Pub. L. No. 100-578, 102 Stat. 2903 (codified at 42 U.S.C. § 263a);
186. Prebula, supra note 130, at 16.
187. See Bouchie, Aaron, MDx: A Murky Brew, BIOCENTURY (Jan. 26. 2009), at A1, A2. Analytical validity is a measure of how accurately and consistently the test detects the presence of a specific genotype.
188. SACGHS PHARMACOGENOMICS REPORT, supra note 3, at 32;
189. Gwinn. M. & Khoury, M.J., Epidemiologic Approach to Genetic Tests: Population-Based Data for Preventive Medicine, in HUMAN GENOME EPIDEMIOLOGY (M.J. Khoury & J. Little eds., 2003).
190. See Bouchie, supra note 128, at A2. Clinical utility refers to the device's ability to inform clinical decision making and predict clinical outcomes. Grosse, S.D. & Khoury, M.J., What is the Clinical Utility of Genetic Testing?, 8 GENETIC MEDICINE 448 (2006). Clinical validity means how well the test predicts a given phenotype (i.e., clinical disorder or outcome).
191. SACGHS PHARMACOGENOMICS REPORT, supra note 3, at 32;
192. Gwinn & Khoury, supra note 128.
193. See FDA, CRITICAL PATH OPPORTUNITIES REPORT AND LIST, at R-1 (2006), available at http://www.fda.gov/oc/initiatives/criticalpath/reports/opp-report.pdf;
194. Dooren, Jennifer Corbett, Consortium to Study Genetics, Drug Safety, WALL ST. J. (Sept. 27, 2007);
195. Prebula, Randy, The Ever-Evolving Role of "Companion Diagnostics", FDLI UPDATE, (Sept./Oct. 2008), at 14, 14.
196. See Lesko et al., supra note 6, at 348.
197. See Woodcock, supra note 5, at 95.
198. FDA, GUIDANCE FOR INDUSTRY. PHARMACOGENOMIC DATA SUBMISSIONS 14 (2005) [hereinafter FDA, GUIDANCE ON PHARMACOGENOMIC DATA SUBMISSIONS], available at http://www.fda.gov/cber/gdlns/ pharmdtasub.pdf;
199. Lesko & Woodcock, supra note 18, at 766.
200. Woodcock, supra note 5, at 95.
201. See Lesko & Woodcock, supra note 27, at 22.
202. Woodcock, supra note 5, at 95.
203. Id.
204. SACGHS PHARMACOGENOMICS REPORT, supra note 3, at 96.
205. Biomarkers Definitions Working Group, Biomarkers and Surrogate Endpoints: Preferred Definitions and Conceptual Framework, 69 CLINICAL PHARMACOLOGY & THERAPEUTICS 89, 91 (2001);
206. see also HUTT ET AL., supra note 12, at 640.
207. For example, the HER2 gene is a biomarker for Herceptin efficacy. See supra notes 48-49 and accompanying text.
208. FDA, GUIDANCE ON PHARMACOGENOMIC DATA SUBMISSIONS, supra note 133, at 4, 24.
209. Id. at 4, 17.
210. Id. at 4.
211. Id. at 5, 17.
212. Id. at 4.
213. Id.
214. See infra notes 171-172 and accompanying text.
215. Id.
216. See Goodsaid, Federico & Frueh, Felix W., Implementing the U.S. FDA Guidance on Pharmacogenomic Data Submissions, 48 ENVTL. MOL. MUTAGENESIS 354, 355 (2007).
217. See Goodsaid, Federico & Frueh, Felix W, Biomarker Qualification Pilot Process at the US Food and Drug Administration, 9 AAPS J. E105, E106 (2007).
218. See Goodsaid & Frueh, supra note 150, at E106-07. It is likely that a prospective Phase III trial would be sufficient for validation. However, the huge cost of running these trials is a major roadblock to validating biomarkers.
219. See Roses, supra note 3, at 859.
220. See 21 C.F.R. §§312, 314, 601.
221. See Lesko & Woodcock, supra note 73, at 766.
222. FDA, GUIDANCE ON PHARMACOGENOMIC DATA SUBMISSIONS, supra note 141, at 7.
223. Id. at 14-15.
224. Id. at 5, 8-9(interpreting21 C.F.R.§ 312.23(a));
225. see also 21 C.F.R. §§ 312.30(b), 312.31;
226. Prebula, supra note 130, at 15.
227. FDA, GUIDANCE ON PHARMACOGENOMIC DATA SUBMISSIONS, supra note 141, at 9.
228. Id. at 6, 10-11 (interpreting 21 C.F.R. §§ 314.50, 601.2);
229. see also Prebula, supra note 130, at 15. Basically, PGx data must be submitted with the NDA unless it concerns an exploratory biomarker.
230. FDA, GUIDANCE ON PHARMACOGENOMIC DATA SUBMISSIONS, supra note 141, at 10-11 (interpreting 21 C.F.R. §314.50).
231. Id. (interpreting 21 C.F.R. § 314.50).
232. Id. at 11 (interpreting 21 C.F.R. § 314.81(b)(2)). This data must be submitted in the NDA holder's annual report as synopses or abbreviated reports. Id.
233. HUTT ET AL., supra note 12, at 633.
234. Roses, supra note 3, at 862.
235. See PRICEWATERHOUSECOOPERS, P ERSONALIZED MEDICINE: THE EMERGING PHARMACOGENOMICS REVOLUTION (2005), available at http://www.pwc.com/techforecast/pdfs/pharmaco-wb-x.pdf;
236. Sadee, W, Pharmacogenomics: The Implementation Phase, AAPS PHARMSCI, Vol. 4, Issue 2, at E5 (2002).
237. For example, this was done during the Herceptin Phase III trials. Lesko et al., supra note 6, at 356 ("A well-known example of enrichment is the enrollment of women with breast cancer who overexpress the HER-2 protein in clinical trials of [Herceptin]."). In that case, the sponsor knew that likely responders would have HER2-overexpression. However, like Herceptin, if patients are included or excluded from a clinical trial based upon a PGx biomarker, that PGx data must be included in the drug labeling, and the label will probably be restricted to a subset of patients.
238. See discussion infra Part 3.5.
239. Lesko et al., supra note 6, at 350 ("[T]here is a need to have some confirmation and/or validation before using pharmacogenetics and pharmacogenomics as inclusion/exclusion criteria or for stratification."). Notwithstanding FDA's guidance, sponsors in fact use exploratory biomarkers as a criterion for stratifying patients in clinical trials. Letter from Peter Barton Hutt, Senior Counsel, Covington & Burling LLP, to author (Jan. 10, 2009) (on file with author).
240. Lesko et al., supra note 6, at 350 ("Even after one or two Phase I studies show that a variant in the drug target may affect drug response, there may not be enough information to exclude a population from Phase II studies, unless more is understood about the functional consequences of the genetic variants.").
241. FDA, however, has been inconsistent on this point. The agency has allowed unvalidated biomarkers to be used for patient stratification, though it is not clear when this practice is acceptable. Interview with Peter Barton Hutt, supra note 18.
242. FDA, International Conference on Harmonization; Guidance on General Considerations for Clinical Trials, 62 Fed. Reg. 66,113, 66,118 (Dec. 17, 1997) [hereinafter FDA, Guidance on Clinical Trials] ("The results of a clinical trial should be analyzed in accordance with the plan prospectively stated in the protocol ... .");
243. see also Mandrekar, S.J. et al., Clinical Trial Designs for Prospective Validation of Biomarkers, 5 AM. J. PHARMACOGENOMICS 317 (2005);
244. Evans, Barbara J., What Will it Take to Reap the Clinical Benefits of Pharmacogenomics?, 61 FOOD & DRUG L.J. 753, 759 (2006). For example, the traditional clinical trial is designed to confirm that a drug candidate is safe and effective in the general population, where efficacy is determined by measuring predefined clinical endpoints.
245. Young, Donna, FDA Panel Wrestles with Biomarker Label Concerns, BIOWORLD TODAY (Dec. 17, 2008) (quoting Richard Pazdur, Director, FDA Office of Drug Products) (internal quotation marks omitted), available at http://www.bioworld.com/servlet/com.accumedia.web. Dispatcher?forceid=49565&next=bioWorldToday-article&search=1&prodID= 4&htsid=8&htmax=178.
246. Woodcock, supra note 5, at 100-101 ("[A]ny initial finding in a subset of people, no matter how exciting, must be approached as a hypothesis-generating event that must be confirmed.");
247. Lesko et al., supra note 6, at 354 ("[T]he confirmation of identified genetic associations is mandatory if pharmacogenetic biomarkers are to be included in drug labeling.").
248. FDA, Guidance on Clinical Trials, supra note 169;
249. see also Lesko et al., supra note 6, at 356 ("Associations between genotypes and clinical outcomes can also be explored retrospectively . . . but these are mainly exploratory and would need confirmation in a clinical trial prospectively.");
250. Kulynych, Jennifer, Will FDA Relinquish the "Gold Standard" for New Drug Approval? Redefining "Substantial Evidence" in the FDA Modernization Act of 1997, 54 FOOD & DRUG L.J. 127,141-142 (1999) (discussing FDA's reluctance to using "post hoc subgroup analysis").
251. See Emilien et al., supra note 69, at 394-395;
252. Binzak, supra note 4, at 113.
253. Amur, Shashi et al., Integration and Use of Biomarkers in Drug Development, Regulator and Clinical Practice, 2 BIOMARKERS MED. 305, 310 (2008);
254. see also FDA, DRUG-DIAGNOSTIC CO-DEVELOPMENT CONCEPT PAPER 18 (2005) [hereinafter FDA, DRUG-DIAGNOSTIC CO- DEVELOPMENT] (Stating that in clinical trials for diagnostic assays, "where the analyte is stable and where collection bias ... can be carefully characterized and addressed, prospectively designed retrospective clinical utility studies may be possible."), available at http://www.fda.gov/cder/genomics/pharmacoconceptfn.pdf.
255. Amur, supra note 174, at 309.
256. See id.;
257. Roses, supra note 3, at 862.
258. Smith, Lauren, Committee OKs Retrospective Studies, But With Caveats, PINK SHEET (Dec. 22, 2008), at 27, 27.
259. Id.
260. Id.
261. Id. at 28.
262. See id. at 27.
263. Wang, Shirley S., Erbitux, Vectibix Label Change Approved for KRAS Gene, WALL ST. J. HEALTH BLOG (July 20, 2009), http://blogs.wsj.com/health/2009/07/20/erbitux-vectibix-label-change- approved-for-kras-gene/.
264. Id.
265. This assumes that the PGx test is not already available (e.g., using a commercially available gene chip from a third party). See FDA, GUIDANCE ON PHARMACOGENOMIC DATA SUBMISSIONS, supra note 141, at 6.
266. Prebula, supra note 130, at 15.
267. FDA, GUIDANCE ON PHARMACOGENOMIC DATA SUBMISSIONS, supra note 141, at 15.
268. Gibbs, supra note 113, at 8;
269. Dunn, supra note 7.
270. Gibbs, supra note 113, at 8 ("A company that intends to commercialize an assay for personalized medicine would be well-advised to meet with the Office of In Vitro Diagnostic Device Evaluation and Safety (OIVD) well before beginning clinical studies.").
271. FDA, DRUG-DIAGNOSTIC CO-DEVELOPMENT, supra note 174, at 3.
272. FDA. GUIDANCE ON PHARMACOGENOMIC DATA SUBMISSIONS, supra note 141, at 6,15. For definitions of analytical validity, clinical utility, and clinical validity,
273. see supra notes 128-129.
274. See Prebula, supra note 130, at 16;
275. see also SACGHS PHARMACOGENOMICS REPORT, supra note 3, at 34 ("Not only is it difficult to generate evidence of clinical validity and clinical utility for a PGx test, but also there is little motivation to do so and considerable confusion about what constitutes a demonstration of clinical validity and clinical utility. FDA, for example, does not evaluate clinical validity or clinical utility per se but rather assesses the safety and effectiveness of a device. These parameters generally are tied to an assessment of the analytical and clinical performance of the device."),
276. See Lesko et al., supra note 6, at 349.
277. See id. at 352. The most realistic best case scenario is that the PGx biomarker is discovered during Phase II, and the Phase III trial is used to confirm PGx data for supporting safety, efficacy, and labeling of the drug. Id.
278. Prebula, supra note 130, at 16.
279. See SACGHS PHARMACOGENOMICS REPORT, supra note 3, at 26. Of course, if the drug can be approved for the general population, it is always possible to later modify a drug label to include information about a subsequently developed PGx diagnostic test.
280. Prebula, supra note 130, at 16 ("FDA has acknowledged the agency will accept as supportive data for assay approval, use of retrospective samples that are collected during the drug trial and then later used for the validation of a biomarker.") (citing Steve Gutman, Director, FDA Office of In Vitro Diagnostic Evaluation and Safety, 2007 American Association of Clinical Chemistry Annual Meeting).
281. Interview with Peter Barton Hutt, supra note 18.
282. See Prebula, supra note 130, at 16. Furthermore, the difficulties of co-development are exacerbated by cultural and strategic differences between pharmaceutical and medical device manufacturers.
283. See Keeling & Roth, supra note 63.
284. Also note that where a PGx-based drug is distributed with an IVD assay, FDA may regulate them as a "combination product." FDA defines a combination product as: "A drug, device, or biological product packaged separately that according to its investigational plan or proposed labeling is intended for use only with an approved individually specified drug, device, or biological product where both are required to achieve the intended use, indication, or effect and where upon approval of the proposed product the labeling of the approved product would need to be changed, e.g., to reflect a change in intended use, dosage form, strength, route of administration, or significant change in dose ... ." 21 C.F.R. § 3.2(e)(3). FDA established the Office of Combination Products (OCP) to address the challenge of reviewing products that are neither pure drugs nor pure devices. Bawa, Raj et al., Nanopharmaceuticals: Patenting Issues and FDA Regulatory Challenges, SCITECH LAWYER (Fall 2008), at 10, 11. The agency uses the "primary mode of action" principle to assign a combination product to the appropriate center. Primary mode of action is defined as "the single mode of action of a combination product that provides the most important therapeutic action of the combination product" and mode of action is defined as "the means by which a product achieves its intended therapeutic effect or action." If the primary mode of action of a combination product is that of a drug, then CDER has primary jurisdiction, and if the primary mode of action is that of a device, CDRH has primary jurisdiction.
285. See Safe Medical Devices Act of 1990, Pub. L. No. 101-629, § 16, 104 Stat. 4511 (codified at 21 U.S.C. §353(g));
286. Fed. Reg. 49,848 (Aug. 25, 2005);
287. Assignment of Agency Component for Review of Premarket Applications, 56 Fed. Reg. 58,754, 58,574 (Nov. 21 1991) (codified at 21 C.F.R. pt. 3);
288. Sasjack, supra note 22, at 23.
289. For example, Herceptin has both an IVD and a LDT companion diagnostic test that can be used to test for HER2 over-expression.
290. Gibbs, supra note 113, at 8.
291. See SACGHS PHARMACOGENOMICS REPORT, supra note 3, at 53.
292. Most genetic tests use analyte-specific reagents (ASRs), such as antibodies or nucleic acid sequences, to identify and quantify substances in a patient's biological sample. S.I., Gutman, FDA's Role in the Regulation of In Vitro Diagnostic, Presentation to FDA, CDRH, Office of In Vitro Device Evaluation & Safety (May 10, 2003), available at http://www.fda.gov/ cdrh/oivd/presentations/051003-gutman-1.html.
293. FDA, GUIDANCE FOR INDUSTRY AND FDA STAFF: COMMERCIALLY DISTRIBUTED ANALYTE SPECIFIC REAGENTS (ASRs): FREQUENTLY ASKED QUESTIONS (2007), available at http://www.fda.gov/cdrh/oivd/guidance/1590.pdf.
294. FDA, CDRH, OFFICE OF IN VITRO DIAGNOSTIC DEVICE EVALUATION & SAFETY, DRAFT GUIDANCE FOR INDUSTRY, CLINICAL LABORATORIES, AND FDA STAFF: IN VITRO DIAGNOSTIC MULTIVARIATE INDEX ASSAYS (2007), available at http://www.fda.gov/cdrh/oivd/guidance/1610.pdf.
295. Id. at 8.
296. See Petition from Genentech, Inc. to FDA, Citizen Petition No. 2008-P-0638-0001 (Dec. 5, 2008), available at http://www.regulations.gov/ fdmspublic/component/main?main=DocumentDetail&o=09000064807d4a7e.
297. See Jeffrey Gibbs, Regulatory Pathways for Molecular Dx, GENETIC ENGINEERING & BIOTECHNOLOGY NEWS, (Aug. 1, 2008).
298. See Evans, B.J., Distinguishing Product and Practice Regulation in Personalized Medicine, 81 CLINICAL PHARMACOLOGY & THERAPEUTICS 288 (2007);
299. see also SACGHS PHARMACOGENOMICS REPORT, supra note 3, at 27.
300. See FDA, Table of Valid Genomic Biomarkers 2008, supra note 8.
301. Prebula. supra note 130, at 15;
302. FDA, Table of Valid Genomic Biomarkers 2008, supra note 8. Note that older versions of the Table of Valid Genomic Biomarkers used these four categories, however FDA has dropped this information from recent versions of the table. See FDA, Table of Valid Genomic Biomarkers in the Context of Approved Drug Labels (Aug. 18, 2009) [hereinafter FDA, Table of Valid Genomic Biomarkers 2009], http://www.fda.gov/Drugs/ScienceResearch/ResearchAreas/ Pharmacogenetics/ucm083378.htm (last visited Jan. 1, 2010).
303. FDA, Table of Valid Genomic Biomarkers 2009, supra note 211.
304. Id.
305. FDA, GUIDANCE ON PHARMACOGENOMIC DATA SUBMISSION, supra note 141, at 6.
306. See SACGHS PHARMACOGENOMICS REPORT, supra note 3, at 75.
307. Id. (citing FDA, DRAFT GUIDANCE FOR INDUSTRY & FDA STAFF: PHARMACOGENETIC TESTS & GENETIC TESTS FOR HERITABLE MARKERS (2006), available at http://www.fda.gov/cdrh/oivd/guidance/1549.pdf).
308. See id.
309. FDA, GUIDANCE ON PHARMACOGENOMIC DATA SUBMISSIONS, supra note 141, at 15.
310. Id.
311. Id. at 14-15.
312. While it is beyond the scope of this article to discuss this point in detail, pharmacogenomic data could also be used to rescue drugs that have been withdrawn from the market due to serious adverse reactions. See SACGHS PHARMACOGENOMICS REPORT, supra note 3, at 26. Drugs withdrawn for safety issues are unlikely to be reintroduced unless PGx data show improvements in the risk-benefit ratio.
313. See Shah, R.R., Can Pharmacogenetics Help Rescue Drugs Withdrawn From the Market?, 7 PHARMACOGENOMICS 889 (2006).
314. Shah, J., Economic and Regulatory Considerations in Pharmacogenomics for Drug Licensing and Healthcare, 21 NATURE BIOTECHNOLOGY 747 (2003).
315. SACGHS PHARMACOGENOMICS REPORT, supra note 3, at 28.
316. See Lesko et al., supra note 6, at 351.
317. See supra Part 3.3.
318. See Li. supra note 78.
319. See 21 U.S.C. §355(o);
320. see also HUTT ET AL., supra note 12, at 727.
321. See HUTT ET AL., supra note 12, at 727.
322. See 21 U.S.C. §355(o)(3);
323. see also Schanz, Stephen J., Pharmaceutical Postmarket Review: Fact of Fiction, 62 FOOD & DRUG L.J. 493, 494 (2007).
324. 21 U.S.C. §§ 334, 352(a), 352(z).
325. See also Roses, Allen D., Pharmacogenetics and Future Drug Development and Delivery, 355 LANCET 1358, 1360 (2000) (proposing that "if clinical trials were to enroll only those patients with pharmacogenetics efficacy profiles, regulatory authorities could consider a significantly enhanced surveillance system with provisional marketing approval for patients with 'efficacy' pharmacogenetic profiles").
326. This would make it a Category 1 PGx drug. See supra text accompanying note 211.
327. See 21 C.F.R. § 314.70 (proposed changes to the terms and conditions specified in an approved NDA must be submitted in a supplemental NDA and approved by FDA).
328. Food and Drug Administration Amendments Act of 2007, Pub. L. No. 110-185, 121 Stat. 823 (codified as amended in scattered sections of 21 U.S.C. and 42 U.S.C).
329. See id. § 901, 21 U.S.C. § 355(o).
330. See 21 C.F.R. § 314.510;
331. see also HUTT ET AL., supra note 12, at 710.
332. A "surrogate endpoint" is a clinical endpoint based on something other than morbidity. See id.
333. 21 C.F.R. § 314.500.
334. See 21 U.S.C. § 355(e);
335. C.F.R. § 314.530. The sponsor, however, could object and force the agency to hold a hearing before it withdraws NDA approval. See 21 U.S.C. § 371(e);
336. C.F.R. § 314.530.
337. See, e.g., Lesko et al., supra note 6, at 355 ("Use of genetic biomarkers to exclude individuals or populations at risk for adverse events will require rigorously validated genetic associations, especially for serious toxicity.").
338. See E.R. Squibb & Sons, Inc. v. Bowen, 870 F.2d 678 (D.C. Cir. 1989);
339. see also HUTT ET AL., supra note 12, at 685-691.
340. Orphan Drug Act, Pub. L. No. 97-414, 96 Stat. 2049 (1983) (codified as amended at 21 U.S.C. §§ 360aa-360ee).
341. 21 U.S.C. §360bb(a)(2). The Act also defines a rare disease as any disease where the sponsor has "no reasonable expectation" of recovering the costs of developing and making the drug "from sales of the drug in the United States." Id. However, this path to orphan drug status is almost never used because of the onerous documentation FDA requires to demonstrate the sponsor's inability to recover costs. See Karst, Kurt R., The Rarely Used "Cost Recovery" Path to Orphan Drug Designation and Approval, FDA LAW BLOG (Feb. 1, 2009), http://www.fdalawblog.net/ fdajaw-blog-hyman-phelps/2009/02/the-rarely-used-cost-recovery-path-to-orphan- drug-designation-and-approval.html.
342. Orphan Drug Act, Pub. L. No. 97-414, 96 Stat. 2049 (1983) (codified as amended at 21 U.S.C. §§ 360aa-360ee).
343. See Haffner, Marlene E., Orphan Products-Ten Years Later and Then Some, 49 FOOD DRUG COSM. L.J. 593, 601 (1994) ("For the 70 drugs approved by the FDA in 1993, approval time averaged 33.1 months; the approval time for orphan drugs in that year averaged 12.8 months.").
344. See Haffner, Marlene E. & Kelsey, John V, Evaluation of Orphan Products by the U.S. Food and Drug Administration, 8 INT'L J. TECH. ASSESSMENT HEALTH CARE 647, 647-648 (1992).
345. 24i Karst, Kurt R., FDA Orphan Drug Designations Are On the Rise, FDA LAW BLOG(Feb. 17.2009), http://www.fdalawblog.net/fda-law- blog-hyman-phelps/2009/02/fda-orphan-drug-designations-are-on-the-rise.html;
346. see also FDA, GUIDELINE FOR INDUSTRY: THE EXTENT OF POPULATION EXPOSURE TO ASSESS CLINICAL SAFETY: FOR DRUGS INTENDED FOR LONG-TERM TREATMENT OF NON-LIFE-THREATENING CONDITIONS 4 (1995) ("In some cases, a smaller number of patients may be acceptable, for example, where the intended treatment population is small."), available at http://www.fda.gov/cder/guidance/ichela.pdf.
347. See Loughnot, David, Note & Comment, Potential Interactions of the Orphan Drug Act and Pharmacogenomics: A Flood of Orphan Drugs and Abuses', 31 AM. J. L. & MED. 365, 366 (2005).
348. 21 U.S.C. §360bb(a)(1)-(2).
349. SACGHS PHARMACOGENOMICS REPORT, supra note 3, at 31. At least two practitioners believe that the statute would cover PGx-based drugs with limited labels that reduce the target populations to under 200,000.
350. Interview with Peter Barton Hutt, supra note 18;
351. Interview with Kurt R. Karst, Hyman, Phelps & McNamara, in Wash., D.C (Feb. 25, 2009). Erbitux (cetuximab), a cancer therapy manufactured by ImClone, is currently, the only Category 1 PGx drug that also has orphan drug status. Compare FDA, CUMULATIVE LIST OF DESIGNATED APPROVED ORPHAN PRODUCTS, available at http://www.fda.gov/orphan/designat/allap.rtf,
352. with FDA, Table of Valid Genomic Biomarkers 2008, supra note 8. Erbitux has two indications that include PGx data. In 2004, it was originally approved as a Category 1 PGx drug for treating colorectal cancer. Press Release, FDA, FDA Approves Erbitux for Colorectal Cancer (Feb. 12, 2004), available at http://www.fda.gov/bbs/topics/NEWS/2004/NEW01024.html.
353. Then in 2006, it was also approved as a Category 3 drug for head and neck cancer. Press Release. ImClone Sys. Inc., FDA Approves Erbitux (cetuximab) for Treatment of Head and Neck Cancer (Mar. 1,2006), available at http://phx.corporate-ir.net/phoenix.zhtml?c=97689&p=irol-newsArticle&ID= 824286.
354. It also gained orphan drug status for this second indication. FDA, CUMULATIVE LIST OF DESIGNATED APPROVED ORPHAN PRODUCTS, supra. However, because head and neck cancer only affects 40,000 Americans each year, ImClone did not need to rely on labeling limited by PGx data to get orphan drug status.
355. See Press Release, ImClone Sys. Inc., supra.
356. 21 C.F.R. §316.20(b)(6).
357. E-mail from Kurt R. Karst, Hyman, Phelps & McNamara, to author (Feb. 25, 2009) (on file with author).
358. Id.
359. See 57 Fed. Reg. 62,076, 62,081 (Dec. 29, 1992).
360. See supra text accompanying note 211.
361. A sui generis system could also use a tiered approach, providing varied benefits depending on the category the PGx-based drug falls into. For example, providing a greater benefit to sponsors of Category 1 PGx drugs than to sponsors of Category 2 or 2a drugs.
362. See FDA, CUMULATIVE LIST OF DESIGNATED APPROVED ORPHAN PRODUCTS, supra note 249;
363. SACGHS PHARMACOGENOMICS REPORT, supra note 3, at 30;
364. Milne, Christopher-Paul & Tait, Joyce, Evolution along the Government-Governance Continuum: FDA's Orphan Products and Fast Track Programs as Exemplars of "What Works" for Innovation and Regulation, 64 FOOD & DRUG L.J. 733 ,740 (2009). Prior to the passage of the ODA, only thirty-four orphan drugs were on the market.
365. See Maeder, Thomas. The Orphan Drug Backlash, SCI. AM., (May 2003). at 87.
366. Note that sponsors generally already get several years of marketing exclusivity. The Hatch-Waxman Act grants sponsors four to five years of data exclusivity following approval of the sponsor's NDA, during which time FDA will not accept abbreviated new drug applications (ANDAs) from generic challengers. See HUTT ET AL., supra note 12, at 762. After the data exclusivity period expires, generic challengers may submit ANDAs seeking permission to market generic versions of the sponsor's brand-name drug. Id. Sponsors of unpatented drugs usually get around seven years of effective market exclusivity (five years of data exclusivity plus approximately two years for ANDA approval). Id.;
367. Avery, Matthew, Note, Continuing Abuse of the Hatch-Waxman Act by Pharmaceutical Patent Holders and the Failure of the 2003 Amendments, 60 HASTINGS L.J. 171, 188 (2008). Sponsors of patented drugs usually get 7.5 years of effective market exclusivity. 21 U.S.C. §355(j)(5)(F)(ii). However, actions by FDA or a federal district court can shorten these periods. Avery, supra, at 177. Consequently, the seven years of marketing exclusivity granted by the Orphan Drug Act generally would not provide any benefit over what is already given by the Hatch-Waxman Act. But the guaranteed marketing exclusivity provided by the Orphan Drug Act is arguably more valuable to sponsors than the variable de facto marketing exclusivity created by Hatch-Waxman's data exclusivity and ANDA review scheme.
368. This is similar to the incentive given to sponsors for conducting pediatric studies. See 21 U.S.C. § 355A(b)-(c) (granting a six-month marketing exclusivity extension);
369. see also I. Cohen, Glenn, Therapeutic Orphans, Pediatric Victims? The Best Pharmaceuticals for Children Act and Existing Pediatric Human Subject Protection, 58 FOOD & DRUG LJ.. 661, 663-664 (2003). It is beyond the scope of this article to analyze the appropriate length of time of the increase in exclusive sales.
370. See Kushner, Leslie, Note, Incentivizing Postmarketing Pharmaceutical Product Safety Testing with Extension of Exclusivity Periods, 19 FORDHAM INTELL. PROP. MEDIA & ENT. L.J. 519, 546-547 (2009).
371. But see Loughnot, supra note 247, at 365 (arguing that it would be an abuse of the ODA to apply it to PGx-based drugs).
372. A similar argument could be made for modifying the Humanitarian Device Exemption of the Safe Medical Devices Act of 1990, which is similar to the Orphan Drug Act, except it only applies to drug therapies for patient populations under 4,000 persons. However, the 1990 Act imposes strict price controls that would likely deter any for-profit pharmaceutical company from taking advantage of its provisions. See SACGHS PHARMACOGENOMICS REPORT, supra note 3, at 31.
373. See Woodcock, supra note 5, at 93.
374. See id.
375. SACGHS PHARMACOGENOMICS REPORT, supra note 3, at 95.
376. Lesko, supra note 23, at 815.