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Demanding Individually Safe Drugs Today: Overcoming the Cross-Labeling Legal Hurdle to Pharmacogenomics

Published online by Cambridge University Press:  06 January 2021

Scott Sasjack
Scott Sasjack*
Affiliation:
Boston University School of Law, Emory University, Business Litigation Department, Nixon Peabody, LLP — Boston
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Extract

If new refrigerators hurt 7% of customers and failed to work for another one-third of them, customers would expect refunds … manufacturers would be strictly liable for the injuries, and there would be implied warranties even if the manufacturer made no guarantees.

What if physicians could use genetic tests to tailor prescriptions to their patients’ individual genotypes? Physicians and pharmaceutical companies can use pharmacogenomics to decrease the number of adverse drug reactions, increase drug efficacy, and lower health care costs. Unfortunately, cross-labeling rules serve as both legal and policy hurdles for these advances, hurdles the FDA has the power to remove. Part I explains pharmacogenomics and why it currently has a narrow application. Part II discusses the FDA's regulatory approach to pharmacogenomics. Part III explains the legal and policy hurdles of cross-labeling and how they impede the more widespread use of pharmacogenomics. Part IV examines ways to clear the legal cross-labeling hurdles while Part V examines ways to clear the policy cross-labeling hurdles. Finally, Part VI discusses some of the many other complex legal and policy issues that lawmakers, regulators, and the industry will need to resolve in order to realize the full potential of pharmacogenomics.

Type
Article
Information
American Journal of Law & Medicine , Volume 34 , Issue 1 , March 2008 , pp. 7 - 40
Copyright
Copyright © American Society of Law, Medicine and Ethics and Boston University 2008

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References

1 Evans, Barbara J., Flockhart, David A. & Meslin, Eric M., Creating Incentives for Genomic Research to Improve Targeting of Therapies, 10 Nature Med. 1289, 1289 (2004)CrossRefGoogle ScholarPubMed.

2 Xie, Hong-Guang & Frueh, Felix W., Pharmacogenomics Steps Toward Personalized Medicine, 2 Personalized Med. 325, 326 (2005)CrossRefGoogle ScholarPubMed, (discussing the clinical benefits of recent pharmacogenomic findings) (citing Lazarou, J., Pomaeranz, B.H. & Corey, P.N., Incidence of Adverse Drug Reactions in Hospitalized Patients: A Meta-analysis of Prospective Studies, 279 JAMA 1200 (1998)CrossRefGoogle ScholarPubMed), available at http://www.fda.gov/cder/genomics/publications/Xie2.pdf.

3 Id. at 325 (citing Spear, B.B., Heath-Chiozzi, M. & Huff, J., Clinical Application of Pharmacogenetics, 7 Trends Molecular. Med. 201 (2001)CrossRefGoogle ScholarPubMed); see also Evans, supra note 1, at 1289 (citing T. Peakman et al., Custodians in Crisis: the Impact of Genomics on Regulation, Drug Discovery World, Fall 2001, at 11, 11) (“On average, it is believed that only 60% of prescriptions produce the desired therapeutic benefits.”).

4 Xie, supra note 2, at 325 (citing Dale, P. et al., 10-Hydroxylation of Nortriptyline in White Persons with 0, 1, 2, 3, and 13 Functional CYP2D6 Genes, 63 Clinical Pharmacology Therapeutics 444 (1998)CrossRefGoogle Scholar).

5 Id. at 325.

6 Huang, Shiew-Mei et al., Application of Pharmacogenomics in Clinical Pharmacology, 16 Toxicology Mechanisms & Methods 89, 89 (2006)CrossRefGoogle ScholarPubMed, available at http://www.healthanddna.com/fdapaperwithpolymorphismsandmeds.pdf (discussing factors affecting patients’ responses to drugs); Xie, supra note 2, at 325.

7 Xie, supra note 2, at 325.

8 Id. at 325.

9 Shastry, B.S., Pharmacogenetics and the Concept of Individualized Medicine, 6 Pharmacogenomics J. 16, 17 (2006)CrossRefGoogle ScholarPubMed (encouraging a pharmacogenetic approach in drug development).

10 Human Genome Project, Pharmacogenomics (2006), http://www.ornl.gov/sci/techresources/Human_Genome/medicine/pharma.shtml.

11 Shastry, supra note 9, at 16; see also infra note 36.

12 Huang, supra note 6, at 89-91. Even if multiple genes account for variability in patients’ drug reactions (making the trait polygenetic), a test based on even one of the genes involved can still improve the risk/benefit ratio. Id. at 91.

13 Evans, Barbara J., What Will it Take to Reap the Clinical Benefits of Pharmacogenomics?, 61 Food & Drug L.J. 753, 755 (2006)Google ScholarPubMed (discussing the potential of pharmacogenomics).

14 Id. at 754.

15 U.S. Food & Drug Admin., Guidance for Industry: Pharmacogenomic Data Submissions 4, 17 (March 2005), available at http://www.fda.gov/cder/guidance/6400fnl.pdf; Huang, supra note 6, at 89-91.

16 See infra note 85.

17 Shastry, supra note 9, at 17 (citing Wilkinson, G.R., Drug Metabolism and Variability Among Patients in Drug Response, 352 New Eng. J. Med. 2211 (2005)CrossRefGoogle ScholarPubMed).

18 Id. at 17.

19 Mayo Clinic Staff, Personalized Medicine, Tailoring Treatment to Your Genetic Profile (2006), http://www.mayoclinic.com/health/personalized-medicine/CA00078.

20 Higashi, Mitchell K. et al., Association Between CYP2C9 Genetic Variants and Anticoagulation-Related Outcomes During Warfarin Therapy, 287 JAMA 1690 (2002)CrossRefGoogle ScholarPubMed, available at http://jama.ama-assn.org/cgi/content/full/287/13/1690#REF-JOC11820-13.

21 McWilliam, Andrew, Lutter, Randall & Nardinelli, Clark, Health Care Savings from Personalizing Medicine Using Genetic Testing: The Case of Warfarin 5 n.12 (AEI-Brookings Joint Ctr. for Regulatory Studies, Working Paper No. 06-23, 2006)Google Scholar, available at http://www.aei-brookings.org/admin/authorpdfs/page.php?id=1337.

22 Id. at 3-4.

23 Kirell Lakhman, Days Before Warfarin Label Change, Genelex Debuts DTC Dosing Dx; ASHG's ‘Validity’ Notice Could Help, Pharmacogenomics Rep., Oct. 18, 2006, http://www.genelex.com/pgxreporter.pdf.

24 Xie, supra note 2, at 331.

25 Id.

26 Id. at 329.

27 Id.

28 Id.

29 See Sledge, George W. Jr., What is Targeted Therapy?, 23 J. Clinical Oncology 1614, 1614 (2005)CrossRefGoogle ScholarPubMed (“Targeted therapies in breast cancer (especially those targeting the estrogen receptor and HER-2) have transformed the face of this disease over the past generation.”).

30 Xie, supra note 2, at 332.

31 Id.

32 National Center for Biotechnology Information, One Size Does Not Fit All: The Promise of Pharmacogenomics (2004), http://www.ncbi.nlm.nih.gov/About/primer/pharm.html.

33 The promise of pharmacogenomics was a major expectation of the Human Genome Project. See Lesko, Lawrence J. & Woodcock, Janet, Translation of Pharmacogenomics and Pharmacogenetics: A Regulatory Perspective, 3 Nature Reviews Drug Discovery 763, 767 (2004)CrossRefGoogle ScholarPubMed.

34 Human Genome Project, supra note 10; see also Huang, supra note 6, at 90 (listing drugs withdrawn from the U.S. market between 1997 and 2004 as a result of serious adverse drug reactions).

35 McWilliam, supra note 21, at 11-12. The study assumed that two million Americans start taking warfarin each year and that one third of Americans has a variation of the CYP2C9 gene associated with slower metabolization of warfarin (CYP2C9*2 or CYP2C9*30). Id. at 4-5. The study calculated net health care savings as follows: $1.15 billion in reduced bleeding costs + $675 million in reduced stroke costs – $700 million in genetic testing costs. Id. at 12.

36 The correct dose is currently determined by trial and error: “monitoring the level of anticoagulation through blood tests and altering the dose if it is too high or too low.” Id. at 2.

37 See supra text accompanying notes 2 and 3.

38 Evans, supra note 1, at 1289.

39 Ernst, Frank R. & Grizzle, Amy J., Drug-Related Morbidity and Mortality: Updating the Cost-of-Illness Model, 41 J. Am. Pharmaceutical Ass’n. 192 (2001)Google ScholarPubMed.

40 Classen, David C., et al., Adverse Drug Events in Hospitalized Patients: Excess Length of Stay, Extra Costs, and Attributable Mortality, 277 JAMA 301, 305 (1997)CrossRefGoogle ScholarPubMed, described in Xie, supra note 2, at 326.

41 Bero, Lisa A. et al., Characterization of Geriatric Drug-Related Hospital Readmissions, 29 Med. Care 989 (1991)CrossRefGoogle ScholarPubMed.

42 Mark A. Rothstein, Epilogue: Policy Prescriptions, in Pharmacogenomics: Social, Ethical and Clinical Dimensions 319, 332 (Mark. A. Rothstein ed., 2003). Congress enacted the Orphan Drug Act of 1983 in order to create economic incentives for pharmaceutical companies to develop drugs for diseases affecting less than 200,000 Americans because otherwise companies had no economic incentive. Id. Rothstein argues that Congress should reconsider the Orphan Drug Act and create flexibility so that the Act's economic rewards can be granted to products for “orphan genotypes.” Id.

43 The UK Pharmacogenetics Study Group, Policy Issues in Pharmacogenetics; Policy Briefing From the UK Pharmacogenetics Study Group, July 2006, 10, available at http://www.york.ac.uk/res/pgx/publications/PGxpolicyissues2006.pdf (“Although regulatory agencies in the US and, to a lesser extent the EU, are driving the translation of pharmacogenetics into clinical practice, adoption is slow; interviews suggest that regulators themselves are increasingly pessimistic about the speed of uptake.”); Lesko, supra note 33, at 767 (“there has been relatively little translation of [pharmacogenomic] information into drug development and even less into clinical practice.”); Xie, supra note 2, at 332 (“there is a very slow translation of pharmacogenomic information into patient care, and pharmacogenetic testing for drug metabolizing enzymes is still rarely performed in clinical practice”).

44 Woelderink, A., Ibarreta, D., Hopkins, M.M. & Rodriguez-Cerezo, E., The Current Clinical Practice of Pharmacogenetic Testing in Europe: TPMT and HER2 as Case Studies, 6 Pharmacogenomics J. 3, 3 (2006)CrossRefGoogle ScholarPubMed.

45 Chris Womack, One Year Off the Blocks, Roche's AmpliChip Still Shows Slow Adoption, Reimbursement, Pharmacogenomics Rep., Sept. 6, 2006.

46 Id.; infra note 202 and accompanying text.

47 Evans, supra note 1, at 1289.

48 Id.

49 Stuart Hogarth, et al., Regulating pharmacogenomics: An overview of developments in various countries and industry response to regulatory initiatives: A report for Health Canada 46 (2006), available at http://www.phpc.cam.ac.uk/epg/pgx.pdf.

50 C.E. Reeder & W. Michael Dickson, Economic Implications of Pharmacogenomics, in Pharmacogenomics, supra note 42, at 229, 232.

51 Hogarth, supra note 49, at 46.

52 Reeder, supra note 50, at 232.

53 Id.

54 Id.

55 Id. at 230; see also David W. Feigal & Steven I. Gutman, Drug Development, Regulation, and Genetically Guided Therapy, in Pharmacogenomics, supra note 42, at 99, 100; Lesko, supra note 33, at 764.

56 Reeder, supra note 50, at 230.

57 Id. (citing Michelson, S. & Joho, K., Drug Discovery, Drug Development and the Emerging World of Pharmacogenomics: Prospects for Information in a Data Rich Landscape, 2 Current Opinion Molecular Therapeutics 651 (2000)Google Scholar).

58 Id. at 231.

59 Id. at 232.

60 “‘Tailor-made medicines are absurd to the point of being ridiculous’ [said William Haseltine, chairman of Human Genome Sciences, a Rockville, Md., pharmaceutical firm] maintaining that no firm, already reeling from the costs of developing new drugs, would seek to develop five complementary drugs to treat a single disease. The goal should continue to be one drug for one disease, Haseltine said, a strategy his company is pursuing by analyzing genetic activity in the laboratory to identify and produce natural hormones, proteins and antibodies.” Byron Spice, Pharmacogenomics: One Day, it May Allow Doctors to Tailor Drugs to Individuals, Pittsburgh Post-Gazette, July 9, 2000, at A0, available at http://www.post-gazette.com/healthscience/20000709pharmacogenomics.asp.

61 See infra note 66 and accompanying text.

62 See supra note 51 and accompanying text.

63 Reeder, supra note 50, at 231-32. Recent product removals represent $1 to $1.5 billion in lost research investments. Id. at 232.

64 Lesko, supra note 33, at 764.

65 Evans, supra note 13, at 758.

66 Id. at 759. Positive associations between a drug and a subgroup retrospectively discovered in the data may not prove those associations. Id. New prospective clinical trials controlling for biases are necessary to establish safety and efficacy in that subgroup. Id.

67 Id.

68 Id.

69 For example, physicians may administer Herceptin instead of alternative therapies for the sub-population of breast cancer patients in which it has been shown to be more effective than other therapies. See supra notes 26-29 and accompanying text.

70 See Feigal, supra note 55; supra note 69 and accompanying text; but see Reeder, supra note 50, at 233 (“[T]he existence of ‘niche’ therapeutic categories will present an opportunity for smaller, genetics-based biotechnology firms to enter the market and produce the drugs … . In effect, the pharmacogenomics industry may be composed of two sectors: large companies that research, develop, and produce products for high-prevalence polymorphisms and a second ‘cottage’ sector that serves the ‘orphan drug’ market.”).

71 Restatement (Third) of Torts: Products Liability § 6(c) (1998).

72 Williams v. Ciba-Geigy, 686 F. Supp. 573, 577-78 (W.D. La. 1988), aff’d mem., 864 F.2d 789 (5th Cir. 1988) (“[I]t is presumptively inappropriate for a jury to apply the pure risk-utility test of “unreasonably dangerous per se” to a known and warned-of risk of a prescription drug. Such risks have already been considered in the arduous risk-utility scrutiny of the expert Food and Drug Administration's approval procedures … . [T]he court must require, as a part of the plaintiff's burden of producing evidence, an articulable basis for disregarding the FDA's determination that the drug should be available. For instance … evidence tending to show that FDA approval was based on erroneous data or on an assumption that the incidence of harmful effects would be significantly lower than the actual incidence the plaintiff can objectively demonstrate. Or … evidence tending to show that notwithstanding the utility of the drug, the qualitative and quantitative harmful effects, although known and warned of, are such that reasonable minds could conclude that the FDA manifestly erred in its finding that the societal benefits of access to the drug are not outweighed by the risks.”).

73 U.S. Food & Drug Admin., Mission Statement, available at http://www.fda.gov/opacom/morechoices/mission.html.

74 Woodcock, Janet, FDA Policy on Pharmacogenomic Data in Drug Development, 66 La. L. Rev. 91, 98 (2005)Google Scholar.

75 Lesko, Lawrence J. et al., Pharmacogenetics and Pharmacogenomics in Drug Development and Regulatory Decision Making: Report of the First FDA-PWG-PhRMA-DruSafe Workshop, 43 J. Clinical Pharmacology 342, 342 (2003)CrossRefGoogle ScholarPubMed, available at http://jcp.sagepub.com/cgi/reprint/43/4/342.pdf.

76 U.S. Food & Drug Admin., Draft Guidance for Industry: Pharmacogenomic Data Submissions (Nov. 2003), available at http://www.fda.gov/cder/guidance/5900dft.pdf.

77 U.S. Food & Drug Admin., supra note 15, at 14; Lesko, supra note 33, at 766; Woodcock, supra note 74, at 100.

78 U.S. Food & Drug Admin., supra note 15, at 2, 14.

79 Id. at 1.

80 Id. at 2 (“Sponsors submitting or holding [investigational new drug applications] INDs, [new drug applications] NDAs, or [biologics license applications] BLAs are subject to FDA requirements for submitting to the Agency data relevant to drug safety and effectiveness (including 21 CFR 312.22, 312.23, 312.31, 312.33, 314.50, 314.81, 601.2, and 601.12).”).

81 Id. at 15.

82 Id. at 3-4, 16; see also Woodcock, supra note 74, at 100 (“[W]e must acknowledge that there is a tremendous amount of hype involved [with pharmacogenomics]. The reality is that it takes time and effort to verify the validity of any observed association.”).

83 Id. at 17 (“A biomarker that is measured in an analytical test system with well-established performance characteristics and for which there is widespread agreement in the medical or scientific community about the physiologic, toxicologic, pharmacologic, or clinical significance of the results.”).

84 Id. at 17-18 (“A biomarker that is measured in an analytical test system with well-established performance characteristic and for which there is a scientific framework or body of evidence that appears to elucidate the physiologic, toxicologic, pharmacologic, or clinical significance of the test results. A probable valid biomarker may not have reached the status of a known valid marker because, for example, of any one of the following reasons: - The data elucidating its significance may have been generated within a single company and may not be available for public scientific scrutiny. – The data elucidating its significance, although highly suggestive, may not be conclusive. – Independent verification of the results may not have occurred.”).

85 Exploratory biomarkers lack the evidence to be considered known valid or probable valid biomarkers. See Food & Drug Admin., supra note 15, at 5 (“Many pharmacogenomic testing programs implemented by pharmaceutical sponsors or by scientific organizations are intended to develop the knowledge base necessary to establish the validity of new genomic biomarkers … test results are not useful in making regulatory judgments pertaining to the safety or effectiveness of a drug and are not considered known or probable valid biomarkers.”); Huang, supra note 6, at 91.

86 During the IND phase, the sponsor must submit data if: (1) “The test results are used for making decisions pertaining to a specific clinical trial or in an animal trial used to support safety (e.g. the results will affect dose and dose schedule selection, entry criteria into a clinical trial safety monitoring, or subject stratification); (2) A sponsor is using the test results to support scientific arguments pertaining to … dosing and dosing schedule, or the safety and effectiveness of the drug”; (3) the data concerns a known valid biomarker. Food & Drug Admin., supra note 15, at 8-9 (interpreting 21 C.F.R. § 312.23(a)(8) (2007) (A sponsor that intends to conduct a clinical investigation must submit with the IND application “adequate information about pharmacologic and toxicological studies of the drug involving laboratory animals or in vitro, on the basis of which the sponsor has concluded that it is reasonably safe to conduct the proposed clinical investigations”), § 312.23 (a) (9) (A sponsor must submit a summary of previous human experience with the drug known to the applicant including information relevant to the evaluation of the safety of the drug), § 312.23(a)(10)(iv) (A sponsor must submit any other information that would aid evaluation of the safety and design of the proposed clinical trial), and § 312.23(a)(11) (a sponsor must submit “any other relevant information needed for review of the application” if requested by FDA)).

During the NDA and BLA phases, sponsors must submit data if: (1) the sponsor intends to use the data in the drug label or to support scientific arguments made by the sponsor about drug dosing, safety, patient selection or monitoring, or if pharmacogenomic tests are essential to achieving the dosing, safety, or effectiveness described in the labeling, (2) the data concerns a known valid biomarker, or (3) the data concerns a probable valid biomarker. The guidance also recommends submission of a synopsis of exploratory data. Id. at 10, 11 (interpreting 21 C.F.R. § 314.50 (2007)) (“[T]he NDA application is required to contain reports of all investigations of the drug product sponsored by the applicant, and all other information about the drug pertinent to an evaluation of the application that is received or otherwise obtained by the applicant from any source.”), and 21 C.F.R. § 601.2 (2007) (BLA manufacturers must “submit data derived from nonclinical laboratory and clinical studies that demonstrate that the manufactured product meets prescribed requirements of safety, purity, and potency”).

After an NDA or BLA is approved, a sponsor must submit data concerning known or probable valid biomarkers in the annual report as synopses or abbreviated reports. Id. at 11 (interpreting Applications for FDA Approval to Market a New Drug, 21 C.F.R. § 314.81(b)(2) (2007) (The sponsor must annually submit a report containing a “brief summary of significant new information from the previous year that might affect the safety, effectiveness, or labeling of the drug product.”); Changes to an Approved Application, 21 C.F.R. § 601.12 (2007) (A BLA manufacturer “must inform the [FDA] … about each change in the product, production process, quality controls, equipment, facilities, responsible personnel, or labeling established in the approved license application(s).”)).

87 U.S. Food & Drug Admin., supra note 15, at 8-11; see also id. at 4, n.4 (“[T]he term regulatory decision making, as defined here, applies to decisions that FDA may make in the evaluation of pharmacogenomic information used to establish the dosing, safety, or effectiveness of a drug or biological product.”).

88 Id. at 14.

89 See id. The Interdisciplinary Pharmacogenomic Review Group (IPRG) will review the data.

90 Id. at 7-8 (these benefits include the opportunity for sponsors to obtain informal assessments of the data and feedback from FDA concerning drug development, to obtain insight into FDA's evolving regulatory approach to pharmacogenomics, to educate FDA scientists with novel pharmacogenomic studies, and to contribute to a data repository to advance the science of pharmacogenomics and the development of regulatory policy).

91 Id. at 6, 15 (co-development is recommended because FDA cannot approve a drug for which the risk or benefit is predicated on a pharmacogenomic test that is not available for clinical use); see also U.S. Food & Drug Admin., Drug-Diagnostic Co-Development Concept Paper, Draft (2005), available at http://www.fda.gov/cder/genomics/pharmacoconceptfn.pdf (providing technical guidance for co-development).

92 Food & Drug Admin., supra note 15, at 15.

93 Id. at 15, 16.

94 Meeting Notice, 70 Fed. Reg. 15,633-34 (Mar. 28, 2005), available at http://www.fda.gov/ohrms/dockets/98fr/05-5978.pdf.

95 Id. at 15,633.

96 Transcript of the Drug Information Association and the FDA Cross Labeling Workshop: Combination Products and Mutually Conforming Labeling (March 10, 2005), available at http://www.fda.gov/oc/combination/presentations/dia/transcript.html [hereinafter “Transcript.”]

97 See id.

98 Id.

99 21 C.F.R. § 3.2(e)(3) (2007).

100 Transcript, supra note 96; but see id. (“Nobody has defined what individually specified means in any regulation or even in a guidance at the moment. So this is wide open.”) (quoting Anna Longwell); Assignment of Agency Component for Review of Premarket Applications, 56 Fed. Reg. 58,754-58,755 (Nov. 21, 1991) (codified at 21 C.F.R. pt. 3) (The example given of a combination product only refers to a “specific” drug and makes no mention of brand: “[F]or example, a device to aerosolize medication that works only with a specific drug that when given as an aerosol must be used with this device and that, as a consequence, is labeled for this route of administration using only this device.”).

101 See Advanced Medical Technology Association (“AdvaMed”), Comments to FDA Regarding Combination Products and Cross-Labeling, Docket No. 2005N-0098, July 8, 2005, at 20, available at http://www.fda.gov/ohrms/dockets/dockets/05n0098/05n-0098-c000002-vol1.pdf [hereinafter “AdvaMed”] (For example, product liability concerns are not strongly implicated here for company A since A is only one of many manufacturers that makes the product B is sold to work with). See infra text accompanying notes 212-218 for a discussion of the liability issues that otherwise might arise for A.

102 21 C.F.R. § 3.2(e)(3) (2007); Transcript, supra note 96.

103 Id. § 3.5.

104 U.S. Food & Drug Admin., 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 [hereinafter “Intercenter Agreement.”]

105 Transcript, supra note 96; see also Combination Product Coalition (CPC), Comments to FDA Regarding Combination Products and Mutually Conforming Labeling, FDA docket no. 2005N-0098, July 8, 2005, available at http://www.fda.gov/ohrms/dockets/dockets/05n0098/05N-0098-EC2-Attach-1.pdf [hereinafter “CPC”] (“FDA simply has no legal grounds for telling a drug manufacturer that it must relabel its drug in order for the agency to approve a device that would then take advantage of the expanded scope of the drug labeling.”).

106 CPC, supra note 105, at 1.

107 Id. at 7.

108 Id. at 8-9.

109 Id. at 9 (“(1) The likelihood that product A will be changed in the future. (2) The consequences of possible changes to product A … . (3) The effectiveness of company B's ability to monitor product A for such changes. (4) The ability of company B to effectively label the combined use without the need to relabel product A. (5) The ability of company B to respond to changes to product A in a timely manner. (6) Any other issues that bear on the ability of company B to assure the safety and effectiveness of the combined product without the cooperation of company A.”).

110 Id.

111 CPC, Comments to FDA Regarding Combination Products and Mutually Conforming Labeling, FDA docket no. 2005N-0098, Jan. 11, 2006, at 3-4, available at http://www.fda.gov/ohrms/dockets/dockets/05n0098/05n-0098_emc-000002-02.pdf.

112 Transcript, supra note 96 (“I do want to stress that we don't see FDA's role as a broker [of business deals] and urge a lot of caution.”) (quoting David Eveleth); id (quoting Anna Longwell).

113 Id.

114 Id. (David Eveleth).

115 Transcript, supra note 96; see also AdvaMed, supra note 101, at 14-16.

116 AdvaMed, supra note 101, at 19.

117 Id. at 15.

118 Transcript, supra note 96; AdvaMed, supra note 101, at 15-16. “But user fees, under the Prescription Drug User Fee Act, at least, is a zero-sum game. Basically, you just redistribute who pays. So what you are saying is that everybody else in the industry should bear the cost of paying the cost for the benefits and incentives that you are providing to a small number of firms.” Transcript, supra note 96 (quoting Jane Axelrad).

119 AdvaMed, supra note 101, at 10-14, 20 (Whether A's product is branded matters because if it is not, then A is only one of multiple companies that B's device is used with and A's liability exposure will be less.).

120 Id. at 27-28, 33-34.

121 Id. at 34.

122 CPC, supra note 105, at 6.

123 CPC, supra note 111, at 4.

124 Id. (citing 21 C.F.R. § 3.2(e)(3)(2006)).

125 Id.

126 Id.

127 CPC, supra note 105, at 8; CPC, supra note 111, at 4. The CPC believes that FDA should avoid even asking companies to cooperate. See CPC, supra note 105, at 8. “FDA should not apply any pressure on a company to work with another. We have asked a number of companies what they would consider to be pressure, and it appears that companies have a low threshold for feeling pressure by the regulatory agency that governs so much of what they do. We believe that FDA should ask for cooperation from reluctant parties very lightly and frankly in rare circumstances where there is no risk of pressure.” CPC, supra note 105, at 6.

128 “What does it mean that ‘labeling of the approved product would not need to be changed?’ [in 21 C.F.R. § 3.2(e)(3)] This is the critical question because this language determines whether Product B can be approved without the cooperation of Company A. Can we develop criteria that will allow the agency to find that in some cases, the labeling will not need to be changed?” Nancy Stade, Assoc. Chief Counsel, Devices, FDA, Legal Considerations in Cross Labeling Policy, PowerPoint Presentation Before the FDA/DIA, Combination Products and Mutually Conforming Labeling Workshop, 25 (May 10, 2005) (presentation available at http://www.fda.gov/oc/combination/presentations/dia/dia05_10.html).

129 Transcript, supra note 96 (the first half of the workshop was devoted to a discussion of these public health issues).

130 If the other drug is off patent and thus made by many manufacturers, there is no combination product issue because 21 C.F.R. § 3.2(e)(3) is not triggered since B's device would not “specifically identify” the drug. There is also no combination product issue if the genetic test shows a contraindication for an entire class of drugs, such as sulfites.

131 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).

132 Secretary refers to the Secretary of the Department of Health and Human Services (HHS). See infra note 133.

133 Safe Medical Devices Act of 1990, Pub. L. No. 101-629, § 16, 104 Stat. 4511 (codified at 21 U.S.C. 353(g)) [hereinafter “SMDA”]. Section sixteen in its entirety:

SEC. 16. REVIEW OF MARKET APPLICATIONS FOR ARTICLES COMPRISING COMBINATIONS OF DRUGS, DEVICES, AND BIOLOGICS.

  • (a) REVIEW. – Section 503 (21 U.S.C. 353 is amended - - by striking out the section heading and inserting in lieu thereof the following:

    ‘EXEMPTIONS AND CONSIDERATION FOR CERTAIN DRUGS, DEVICES, AND BIOLOGICAL PRODUCTS’,

    And

    (2) by adding at the end the following:

    • ‘(f)(1) The Secretary shall designate a component of the Food and Drug Administration to regulate products that constitute a combination of a drug, device, or biological product. The Secretary shall determine the primary mode of action of the combination product. If the Secretary determines that the primary mode of action is that of - -

      • ‘(A) a drug (other than a biological product), the persons charged with premarket review of drugs shall have primary jurisdiction,

      • ‘(B) a device, the persons charged with premarket review of devices shall have primary jurisdiction, or

      • ‘(C) a biological product, the persons charged with premarket review of biological products shall have primary jurisdiction.

    • ‘(2) Nothing in this subsection shall prevent the Secretary from using any agency resources of the Food and Drug Administration necessary to ensure adequate review of the safety, effectiveness, or substantial equivalence of an article.

    • ‘(3) The secretary shall promulgate regulations to implement market approval procedures in accordance with paragraphs (1) and (2) not later than 1 year after the date of enactment of this subsection.”

    • ‘(4) As used in this subsection:

      • ‘(A) the term ‘biological product’ has the meaning given the term in section 351(a) of the Public Health Service Act (42 U.S.C. 262(a)).

      • ‘(B) The term ‘market clearance’ includes –

        • ‘(i) approval of an application under section 505, 507, 515, or 520(g),

        • ‘(ii) a finding of substantial equivalence under this subchapter, and

        • ‘(iii) approval of a product or establishment license under subsection (a) or (d) of section 351 of the Public Health Service Act (42 U.S.C. 262).’.

  • (b) DEFINITIONS. – Section 201 (21 U.S.C. 321) is amended - -

    • (1) in paragraph (g)(1), by striking out ‘;but does not include devices or their components, parts, or accessories’, and

    • (2) in paragraph (h)(3), by striking out ‘any of its principal’ and inserting in lieu thereof ‘its primary’.

134 Id. at 4526.

135 Id.

136 Id.

137 136 Cong. Rec. 28251-58 (1990) (passing H.R. 3095, 101st Cong. (1st. Sess. 1990)) (later enacted as Pub. L. No. 101-629).

138 136 Cong. Rec. 28958-63 (1990) (amending H.R. 3095 by substituting the entire text with the text of S. 3006, 101st Cong. (1st Sess. 1990)). Section twenty of S. 3006 contained the language that later became section sixteen of the Act.

139 “The Senate amendment but not the House bill described the general procedures for determining the appropriate component of the FDA to review premarket submissions for products that are comprised of any combination of drugs, devices, or biologicals. The conference agreement reflects the Senate provision.” H.R. Rep. No. 101-959, at 29 (1990) (Conf. Rep.), as reprinted in 1990 U.S.C.C.A.N. 6327, 6334.

140 136 Cong. Rec. 35430-39 (1990); 136 Cong. Rec. 36162-65 (1990).

141 S. Rep. No.101-513, at 1 (1990).

142 Id.

143 Id. at 30 (emphasis added).

144 Id. at 43 (emphasis added).

145 SMDA, supra note 133, at 4526.

146 Id.

147 See discussion supra Part III (explaining FDA hypothetical).

148 S. Rep. No.101-513, at 43 (emphasis added).

149 See supra text accompanying notes 119-127.

150 SMDA, supra note 133, at 4526 (emphasis added).

151 Id.

152 Id. (emphasis added).

153 Medical Device User Fee and Modernization Act of 2002, Pub. L. No. 107-250 § 204, 116 Stat. 1611 (codified at 21 U.S.C. § 353(g)).

154 21 U.S.C. § 353(g)(4)(A)-(B) (2000 & Supp. 2004).

155 Id. § 353(g)(4)(A) (emphasis added).

156 See discussion supra Part III (explaining FDA hypothetical).

157 21 U.S.C. § 353(g)(4)(A) (2000 & Supp. 2004) (emphasis added). The language repeats this command again in § 353(g)(4)(D): “the Office shall ensure the consistency and appropriateness of postmarket regulation of like products subject to the same statutory requirements to the extent permitted by law” (emphasis added).

158 H.R. Rep. No. 107-728, pt. 1, at 15 (2002) (emphasis added).

159 See supra note 98 and accompanying text.

160 Assignment of Agency Component for Review of Premarket Applications, 56 Fed. Reg. 58,754 (Nov. 21, 1991) (codified at 21 C.F.R. pt. 3); see also SMDA, supra note 133, at 4526 (“The secretary shall promulgate regulations to implement market approval procedures in accordance with paragraphs (1) and (2) not later than 1 year after the date of enactment of this subsection.”).

161 21 C.F.R. § 3.1 (2007).

162 Id. § 3.4.

163 Id. § 3.5-3.10. Section 3.5 provides for intercenter agreements between the Center for Biologics Evaluation and Research (CBER), CDRH, and CDER “These guidance documents describe the allocation of responsibility for categories of products or specific products. These intercenter agreements, and any amendments thereto, are nonbinding determinations designed to provide useful guidance to the public.” Id. § 3.5(a)(2). “The availability of any amendments to these intercenter agreements will be announced by Federal Register notice.” Id. § 3.5(a)(1).

164 Id. at §3.2(e):

Combination product includes:

  • (1) A product comprised of two or more regulated components, i.e., drug/device, biologic/device, drug/biologic, or drug/device/biologic, that are physically, chemically, or otherwise combined or mixed and produced as a single entity;

  • (2) Two or more separate products packaged together in a single package or as a unit and comprised of drug and device products, device and biological products, or biological and drug products;

  • (3) 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; or

  • (4) Any investigational drug, device, or biological product packaged separately that according to its proposed labeling is for use only with another individually specified investigational drug, device, or biological product where both are required to achieve the intended use, indication, or effect.

165 Assignment of Agency Component for Review of Premarket Applications, 56 Fed. Reg. 58,754, 58,755 (Nov. 21, 1991) (codified at 21 C.F.R. pt. 3); see also Transcript, supra note 96 (“I was on the writing group for Part 3 and I was also one of the coordinators of getting the CDER-CDRH Agreements in place… . In the preamble, we noted that most of the drugdevice matters would be concomitant use and those did not fall within the area of combination products. So the goal … was to keep the number of products that were … combination products with respect to labeling limited in number and only where it needed to be in place because we, as a writing group [were trying to allow for new technology] … . There is no one left alive that was involved.”) (quoting Leighton Hansel) (emphasis added).

166 See infra note 168.

167 21 C.F.R. § 3.3 (2007) (emphasis added).

168 The rule presents an apparent contradiction. FDA provided that only a narrow class of products should come under the regulations as combination products; but at the same time, it provided that the regulations cover a much broader class that includes products that are not combination products. This can be reconciled by recognizing that the overall purpose of Part 3 is to maximize efficiency. Section 3.1 states that the purpose of including non-combination products under the regulations is to “enhance the efficiency of agency management and operations by providing procedures for determining which agency component will have primary jurisdiction.” Id. § 3.1. FDA wanted to be able to invoke the procedures in Part 3 whenever they are useful in expediting the review process but did not want the procedures to be triggered in cases where they were not useful because primary jurisdiction was not an issue. This would only create additional confusion and would slow down the review process. Thus, FDA expanded the scope of the regulations generally, while providing narrow definitions for combination products.

169 Telephone Interview with Nancy Stade, Office of the Chief Counsel, FDA, in Rockville, Md. (Apr. 3, 2007).

170 But see 21 C.F.R. § 3.2(k) (2007) (“Because combination products are comprised of more than one type of regulated article (biological product, device, or drug), and each constituent part contributes a biological product, device, or drug mode of action, combination products will typically have more than one identifiable mode of action.”). However, this language relates only to determining primary mode of action, an issue that arises even when FDA is only reviewing the device application. See id. Thus, the device alone triggers combination products status, and when FDA reviews the device application, both the device and the drug are considered as components of the combination for the purpose of determining the device's primary mode of action.

171 21 C.F.R. § 3.2(e)(1) is not met because the drug and device are not combined. Sections 3.2(e)(1) and (2) are not met because the drug and device are packaged separately. Section 3.2(e)(4) is not met because the drug is not investigational. Nor is it likely that primary jurisdiction would be “unclear or in dispute” under 21 C.F.R. § 3.3(b), since the drug was already approved and regulated as a drug.

172 See discussion supra Part III (explaining FDA hypothetical).

173 See Intercenter Agreement, supra note 104, at VII.A.1(a)ii.

174 “These intercenter agreements, and any amendments thereto, are nonbinding determinations designed to provide useful guidance to the public.” 21 C.F.R. § 3.5(a)(2)(2007). “The availability of any amendments to these intercenter agreements will be announced by Federal Register notice.” Id. § 3.5(a)(1); see also 21 U.S.C. § 353(g)(4)(F) (2000) (“In [reviewing the intercenter agreements] the Secretary shall consult with stakeholders and … shall determine whether to continue in effect, modify, revise, or eliminate such agreement … and shall publish in the Federal Register a notice of the availability of such modified or revised agreement … .”); H.R. Rep. No. 107-728 at 40 (2002) (“It is the committee's intent that the Office shall not be bound by any existing agreement, guidance or agency practice in determining whether to continue, modify, revise, or eliminate any such agreement … .”).

175 This answers Legal Issue 6 that FDA presented with its hypothetical involving company A and B: “Do the legal issues that arise in the absence of mutually conforming labeling exist independently of § 3.2(e)(3), or can some of these issues be addressed by revisions or clarifications to this part of the definition of a combination product?” Meeting Notice, 70 Fed. Reg. 15,633 –15,634 (Mar. 28, 2005), available at http://www.fda.gov/ohrms/dockets/98fr/05-5978.pdf.

176 See discussion supra Part III (explaining FDA hypothetical).

177 This section of the article discusses regulations that might require the manufacturer of the already approved drug to relabel; but note also that FDA can require the device applicant to label the device in whatever way is necessary to ensure safety and efficacy. 21 U.S.C. § 331(a) (2000) (prohibiting the introduction into interstate commerce of any misbranded device); Id. § 352(f) (stating that a device is misbranded unless its labeling bears adequate directions for use and adequate warnings against uses that might be dangerous to health); Id. § 360c(a)(2) (“the safety and effectiveness of a device are to be determined--(A) with respect to the persons for whose use the device is represented or intended, (B) with respect to the conditions of use prescribed, recommended, or suggested in the labeling of the device, and (C) weighing any probable benefit to health from the use of the device against any probable risk of injury or illness from such use … .”); 21 C.F.R. §§ 801.4, 801.5 (2007) (defining “intended use” and “adequate directions for intended use” for devices respectively); 21 C.F.R. §§ 814.45 (a)(2), 814.45(c) (2007) (FDA may deny a premarket application if the proposed labeling does not comply with Parts 801 or 809 or if the application does not satisfy the safety and effectiveness criteria of § 860.7); 21 C.F.R. § 860.7(d)(1) (2007) (“There is reasonable assurance that a device is safe when … the probable benefits to health from use of the device for its intended uses and conditions of use, when accompanied by adequate directions and warnings against unsafe use, outweigh any probable risks.”).

178 The use of “e.g.” here indicates that the authors of § 3.2(e)(3) saw this as one example of when A might need to relabel, implying that there might be other reasons as well.

179 See Transcript, supra note 96 (David Fox); Telephone Interview with Nancy Stade, supra note 169.

180 21 U.S.C. § 331(b).

181 “A drug or device shall be deemed to be misbranded -- (f) … Unless its labeling bears (1) adequate directions for use; and (2) such adequate warnings against use in those pathological conditions or by children where its use may be dangerous to health, or against unsafe dosage or methods or duration of administration or application, in such manner and form, as are necessary for the protection of users, except that where any requirement of clause (1) of this paragraph, as applied to any drug or device, is not necessary for the protection of the public health, the Secretary shall promulgate regulations exempting such drug or device from such requirement.” Id. § 352. Labeling means “all labels and other written, printed, or graphic matters (1) upon any article or any of its containers or wrappers, or (2) accompanying such article.” 21 U.S.C. § 321(m)(2000). In Kordel, the Court held that the phrase “accompanying such article” is broad enough to include more than just writings on or in the article or package containing the article. Kordel v. United States, 335 U.S. 345, 349 (1948). However, the court emphasized the fact that the literature at issue in the case came from the drug maker. Id. at 348 (“In this case the drugs and the literature had a common origin and a common destination.”).

182 21 C.F.R. § 201.5 (2007).

183 Id. § 201.128.

184 Id.; see also Nat’l Nutritional Foods Ass’n v. Mathews, 557 F.2d 325, 333-34 (2d Cir. 1977) (“In determining whether an article is a ‘drug’ because of an intended therapeutic use, the FDA is not bound by the manufacturer's subjective claims of intent but can find actual therapeutic intent on the basis of objective evidence. Such intent also may be derived or inferred from labeling, promotional material, advertising, and ‘any other relevant source.’” However, “[t]he vendors’ intent in selling the product to the public is the key element in this statutory definition.”) (citations omitted). “No court has ever found that a product is ‘intended for use’ or ‘intended to affect’ within the meaning of the [Act] absent manufacturer claims as to that product's use.” Brown & Williamson Tobacco v. U.S. Food & Drug Admin., 153 F.3d 155, 163 (4th Cir. 1998), aff’d, 529 U.S. 120 (2000) (quoting Coyne Beahm v. U.S. Food & Drug Admin., 966 F. Supp. 1374, 1390 (M.D.N.C. 1997)).

185 21 C.F.R. § 201.5 (2007).

186 Id. § 201.56 (a)(1), (2).

187 Id. § 201.57 (c)(6)(i) (“Warnings and precautions. (i) General. This section must describe clinically significant adverse reactions (including any that are potentially fatal, are serious even if infrequent, or can be prevented or mitigated through appropriate use of the drug), other potential safety hazards (including those that are expected for the pharmacological class or those resulting from drug/drug interactions), limitations in use imposed by them (e.g., avoiding certain concomitant therapy), and steps that should be taken if they occur (e.g., dosage modification). The frequency of all clinically significant adverse reactions and the approximate mortality and morbidity rates for patients experiencing the reaction, if known and necessary for the safe and effective use of the drug, must be expressed as provided under paragraph (c)(7) of this section. In accordance with section 314.70 and 601.12 of this chapter, the labeling must be revised to include a warning about a clinically significant hazard as soon as there is reasonable evidence of a causal association with a drug; a causal relationship need not have been definitely established.”).

188 21 C.F.R. § 201.57 (c)(6)(i) (2007).

189 “A specific warning relating to a use not provided for under the “Indications and Usage” section may be required by FDA in accordance with sections 201(n) and 502(a) of the act if the drug is commonly prescribed for a disease or condition and such usage is associated with a clinically significant risk or hazard.” Id. (emphasis added).

190 Id.; Food Drug and Cosmetic Act § 502(a), 21 U.S.C. § 352(a) (2000) (“A drug or device shall be deemed to be misbranded … if its labeling is false or misleading in any particular.”); Food Drug and Cosmetic Act § 201(n), 21 U.S.C. 321(n) (2007) (“in determining whether the labeling or advertising is misleading there shall be taken into account … not only representations made or suggested by statement, word, design, device, or any combination thereof, but also the extent to which the labeling or advertising fails to reveal facts material … under such conditions of use as are customary or usual”) (emphasis added).

191 See discussion supra Part III (explaining FDA hypothetical).

192 FDA is still developing policy concerning when approving B's device might create a new intended use for A's drug. Telephone Interview with Nancy Stade, supra note 169.

193 See supra notes 183-184 and accompanying text.

194 See id.

195 Assignment of Agency Component for Review of Premarket Applications, 56 Fed. Reg. 58,754, 58,755 (Nov. 21, 1991) (codified at 21 C.F.R. pt. 3).

196 See supra notes 187-188 and accompanying text.

197 See supra notes 185-186 and accompanying text.

198 Additionally, if misuse of the combination is associated with a risk, then FDA can require warnings concerning the proper use of the combination. See supra notes 189-190 and accompanying text.

199 See supra note 105 and accompanying text.

200 See Intercenter Agreement, supra note 104, at VII.A.1(a)ii. True, the intercenter agreement also requires mutually conforming labeling, but this agreement is nonbinding guidance that the FDA can amend. See supra note 174.

201 Transcript, supra note 96 (quoting John Jenkins).

202 “Many doctors are unfamiliar with tests, Dr. Valdes said. Some say that their usefulness has not been proven and that it is not always clear how much to raise or lower a dose based on the test results.” Andrew Pollack, A Special Drug Just for You, At the End of a Long Pipeline, N.Y. Times, Nov. 8, 2005, at F1.

203 Requirements on Content and Format of Labeling for Human Prescription Drugs and Biologics, 65 Fed. Reg. 81,082, 81,082, (proposed Dec. 22, 2000) (to be codified at 21 C.F.R. pt. 201).

204 Noah, Lars & Noah, Barbara A., Law, Medicine, and Medical Technology: Cases and Materials 312 (Clark, Robert C. et al. eds., Foundation Press, 2002)Google Scholar.

205 Noah, Lars, The Coming Pharmacogenomics Revolution: Tailoring Drugs to Fit Patients’ Genetic Profiles, 43 Jurimetrics J. 1, 23 (2002)Google ScholarPubMed (citing Smalley, Walter et al., Contraindicated Use of Cisapride: Impact of Food and Drug Administration Regulatory Action, 284 JAMA 3036, 3036-37 (2000)CrossRefGoogle ScholarPubMed (Finding that when FDA revised the black-box warning for Propulsid (R) (cisapride) and ordered the manufacturer to send 800,000 letters to communicate that this heartburn remedy can cause serious cardiac side effects, these efforts had no “material reduction” in the contraindicated uses of the drug); Evans, Edward et al., Does a Mailed Continuing Education Package Improve Physician Performance? Results of a Randomized Trial in Antihypertensive Care, 255 JAMA 501, 504 (1986)CrossRefGoogle Scholar; Soumerai, Stephen B.> et al., Improving Drug Prescribing in Primary Care: A Critical Analysis of the Experimental Literature, 67 Milbank Q. 268, 293-94 (1989)CrossRefGoogle ScholarPubMed; Woosley, Raymond, Opportunities in Phase IV to Improve Drug Development, 52 Food & Drug L.J. 185, 187 (1997)Google ScholarPubMed).

206 Noah, supra note 204, at 312 (citing Woosley, Raymond L, Drug Labeling Revisions – Guaranteed to Fail?, 284 JAMA 3047, 3047-48 (2000)CrossRefGoogle Scholar (adding that “[i]n the last 25 years, the package inserts for new drugs have increased in length more than 5-fold. For example, the 2-page package insert for cisapride, when printed in 12 point font on 8.5 x 11 paper, is more than 10 pages long and contains more than 470 facts about the drug. Practicing physicians would have difficulty mastering all of this information for even one drug, much less the 40 to 100 medications that they regularly prescribe.”)).

207 Transcript, supra note 96 (David Eveleth: “[P]hysicians are going to be guided by the literature far more than they are going to be guided by the label, with all due respect to the FDA.” Paul M. Goldfarb: “[F]or many of us, [clinicians,] we look at the indications for use that come with the products that we receive in two ways. One, usually the print is too small to deal with it and, secondly, it becomes the rate-limiting step … . [Y]our reference to it is, am I going to get into trouble if I do something at variance[?] […] I don't think we use it as going to it to know what to do with the product so much as we go to it to figure out what not to do.” Ray Tessy: “[A]t least in my experience, there is far more emphasis … on the use of medical literature … [and the literature] very much drive[s] clinical decision-making and use of products over the labeling. In fact, sometimes the labeling becomes often a secondary consideration if there are other sources which are felt to be high-quality sources.”).

208 Evans, supra note 13, at 782.

209 See supra note 177 and accompanying text.

210 Evans, supra note 13, at 782-83.

211 See supra notes, 176-200 and accompanying text.

212 Transcript, supra note 96 (quoting Ray Tessy).

213 See discussion supra Part III (explaining FDA hypothetical).

214 See Transcript, supra note 96.

215 AdvaMed, supra note 101, at 19.

216 See infra text accompanying note 220.

217 See supra notes 71-72 and accompanying text.

218 See supra notes 176-200 and accompanying text.

219 CPC, supra note 105, at 6; see also Evans, supra note 13, at 786; supra discussion Part III (explaining FDA hypothetical).

220 See supra notes 11-16 and accompanying text.

221 The FDA should regulate only B as a combination product. See discussion supra note 169.

222 See discussion supra Part III (explaining FDA hypothetical).

223 Lanham Act, 15 U.S.C. § 1114 (1)(a); 15 U.S.C.A. 1125 §§ (c)(1), (c)(2)(b), (c)(2)(c) (West 1998 & Supp. 2007).

224 Hypertherm, Inc. v. Precision Prod., 832 F.2d 697, 700-701 (1st Cir. 1987) (Defendant could use Plaintiff's trademark to advertise its own products as “compatible with” or as replacement parts for Plaintiff's products as long as Defendant made clear that it was the origin of Defendants products); Bijur Lubricating Corp. v. Devco Corp., 332 F. Supp. 2d 722, 732-734 (D.N.J. 2004) (Defendant did not infringe Bijur's s trademark by marketing “Bijur Replacement Parts” because there was no likelihood of confusion as to whether Plaintiff or Defendant manufactured the replacement parts; and Defendant did not dilute Plaintiff's trademark because Defendant “simply us[ed] the ‘Bijur’ name as a point of reference for its own products,” a nominative use); Porter v. Farmers Supply Serv., Inc., 617 F. Supp. 1175, 1187 (D. Del. 1985), aff’d, 790 F.2d 882 (Fed. Cir. 1986) (“Merely specifying that a replacement part will be suitable for use in a product bearing a trademarked name lacks the requisite element of actual or foreseeable deception to the public.”).

225 35 U.S.C. § 271(a) (2007).

226 35 U.S.C. § 271(e)(1) (2007).

227 Merck KGaA v. Integra Lifesciences I, Ltd., 545 U.S. 193, 202 (2005) (“There is simply no room in the statute for excluding certain information from the exemption on the basis of the phase of research in which it is developed or the particular submission in which it could be included.”).

228 Eli Lilly & Co. v. Medtronic, Inc., 496 U.S. 661 (U.S. 1990); AbTox Inc. v. Exitron Corp., 122 F.3d 1019, 1028-1029 (Fed. Cir. 1997), amended by, 131 F.3d 1009 (Fed Cir. 1997) (citations omitted) (“The Supreme Court [in Eli Lilly v. Medtronic] interpreted the phrase ‘a Federal law’ to refer to ‘an entire statutory scheme of regulation’ not merely to single sections or subsections related to drugs or veterinary biological products. Therefore, the Court broadly held that section 271(e)(1) applies to any use reasonably related to regulation under the FDCA, which certainly includes Class II devices … . Section 271(e)(1) makes no distinctions based upon the different FDA classes of medical devices or drugs.”); see also Classen Immunotherapies, Inc. v. Biogen Idec, 381 F. Supp. 2d 452, 455-456 (D. Md. 2005) (holding that § 271(e)(1) exempted Defendant's use of Plaintiff's patented method for evaluating vaccine schedules when Defendant conducted post-approval research studies of vaccines to comply with FDA regulations); Wesley Jessen Corp. v. Bausch & Lomb, Inc., 235 F. Supp. 2d 370, 374-376 (D. Del. 2002) (holding that § 271(e)(1) exempted Defendant's use of Plaintiff's patented contact lens materials in Defendant's post approval study of its contact lenses).

229 “‘It is … well settled that each element of a claim is material and essential, and that in order for a court to find infringement, the plaintiff must show the presence of every element or its substantial equivalent in the accused device.’ […] There can be no infringement as a matter of law if a claim limitation is totally missing from the accused device.” London v. Carson Pirie Scott & Co., 946 F.2d 1534, 1538-1539 (Fed. Cir. 1991) (quoting Lemelson v. United States, 752 F.2d 1538, 1551 (Fed. Cir. 1985)).

230 A party is only liable for contributory infringement for selling an article if the purchaser directly infringes the patent. Husky Injection Molding Sys. Ltd. v. R&D Tool & Eng’g Co., 291 F.3d 780, 784 (Fed. Cir. 2002). A physician and a patient that use B's test are well within their rights if they use the test to modify a dosage or forgo using the drug. Absent a contractual limitation, the purchaser of a patented article may modify that article and replace non-patented parts without infringing the patent. “A purchaser is within its rights to modify a machine by substituting a readily replaceable part … .” Id. at 788 (holding that Defendant did not contributorily infringe by selling molds and carrier plates for Plaintiff's injection molding system because Plaintiff's customers did not directly infringe when they installed these parts); Jazz Photo Corp. v. Int’l Trade Comm’n, 264 F.3d 1094, 1102 (Fed. Cir. 2001) (“The purchaser of a patented article has the rights of any owner of personal property, including the right to use it, repair it, modify it, discard it, or resell it, subject only to overriding conditions of the sale.”). A purchaser of a patented article only impermissibly reconstructs the article if he entirely “spends” the original article and then completes a “second creation” of the article. Dana Corp. v. Am. Precision Co., 827 F.2d 755, 758 (Fed. Cir. 1987) (quoting Aro Mfg. Co. v. Convertible Top Replacement Co., 365 U.S. 336, 346 (1961)).

A physician and patient that use B's test would not impermissibly reconstruct the drug because they would not “spend” and then recreate it. They would not replace any parts of the drug and arguably would not even modify the drug by using the test to adjust dosage; although they would be within their rights to do so. The test is merely a separate diagnostic tool. See Beal Corp. Liquidating Trust v. Valleylab Inc., 927 F.Supp.1350, 1362 (Fed. Cir. 1996) (finding that Plaintiff did not contributorily infringe by selling electrosurgical handpiece unit for use with Defendant's patented electrosurgical base unit because the electrosurgeons did not infringe Defendant's patent by using the handpiece). In many cases, the physician would administer the test before even prescribing the drug and thus arguably would not even “use” the patented drug with the test under the Patent Act. See 35 U.S.C. § 271(a) (prohibiting unauthorized “uses” of a patented invention).

231 See discussion supra Part IV.

232 21 U.S.C. § 355(l)(2)(E) (2007) (referencing The Freedom of Information Act, 5 U.S.C. § 552(b)).

233 See Intercenter Agreement, supra note 104, at VII.A.1(a)ii.

234 See U.S. Food & Drug Admin., Draft Guidance for Industry: Applications Covered by Section 505(B)(2) 7-8 (Oct. 1999), available at http://www.fda.gov/cder/guidance/2853dft.pdf (allowing an applicant to reference “past FDA findings of safety and effectiveness for approved drugs,” in an “application for a new combination product in which the active ingredients have been previously approved individually.”).

235 See supra note 232 and accompanying text.

236 Woodcock, supra note 74, at 94.

237 See supra note 51 and accompanying text.

238 See Transcript, supra note 96 (Kathryn Gleason) (“[M]any of the innovator companies in AdvaMed are also Company A so they see these issues both ways. They are very nonparochial about responses to this issue.”).