Pharmaceutical Efficacy: The Illusory Legal Standard

Washington and Lee Law Review, Aug 2018

The very long and expensive process of new drug research and development might suggest to observers that the efficacy standard for drugs is elevated and substantial, but this is not the case. Under the U.S. Federal Food, Drug, and Co smetic Act, new drug approval merely requires that there be “substantial evidence that the drug will have the effect it purports or is represented to have.” While the evidence of effectiveness must therefore be substantial, the efficacy attested to by that evidence need not surpass any particular threshold (other than zero), thus allowing drugs with de minimis efficacy to be approved and sold at market rates. No other concept, principal, or standard applied during the approval process or after changes this result. The “gold standard,” which includes the elements of blinding, randomiza tion, and placebo control, is described in but not required by the drug statute, and in any event addresses various problems related to bias rather than magnitude of efficacy. Similarly, the concept of “statistical significance,” which constitutes an essential element of modern research protocols, addresses the problem of certainty, not degree, of efficacy. The statutory requirement of “clinical significance,” far from ensuring “substantial efficacy,” demands no more than that there be statistical significance in a human study (as opposed to, for example, an animal study). Rather than specifying a fixed level of efficacy or even a flexible standard of efficacy that a drug must possess, the U.S. drug approval framework thus fully delegates to drug companies and to the free market the determination of what level of efficacy is acceptable. The critical implication is that the public (and physicians and insurers) should not rely on the fact of FDA approval as an indication th at medicines, including new and very highly priced ones, possess efficacy that is meaningfully greater than no efficacy at all.

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Pharmaceutical Efficacy: The Illusory Legal Standard

Pharmaceutical Efic acy: The Il lusor y Legal Standard Jonathan J. Darrow 0 1 0 Thi s Article is brought to you for free and open access by the Law School Journals at Washington & Lee University School of Law Scholarly Commons. It has been accepted for inclusion in Washington and Lee Law Review by an authorized administrator of Washington & Lee University School of Law Scholarly Commons. For more information , please contact , USA 1 Jonathan J. Darrow, Pharmaceutical Efic acy: Th e Illusory Legal Standard , 70 Wash. & Lee L. Rev - Pharmaceutical Efficacy: The Illusory Legal Standard Jonathan J. Darrow* The very long and expensive process of new drug research and development might suggest to observers that the efficacy standard for drugs is elevated and substantial, but this is not the case. Under the U.S. Federal Food, Drug, and Cosmetic Act, new drug approval merely requires that there be “substantial evidence that the drug will have the effect it purports or is represented to have.” While the evidence of effectiveness must therefore be substantial, the efficacy attested to by that evidence need not surpass any particular threshold (other than zero), thus allowing drugs with de minimis efficacy to be approved and sold at market rates. No other concept, principal, or standard applied during the approval process or after changes this result. The “gold standard,” which includes the elements of blinding, randomization, and placebo control, is described in but not required by the drug statute, and in any event addresses various problems related to bias rather than magnitude of efficacy. Similarly, the concept of “statistical significance,” which constitutes an essential element of modern research protocols, addresses the problem of certainty, not degree, of efficacy. The statutory requirement of “clinical significance,” far from ensuring “substantial efficacy,” demands no more than that there be statistical significance in a human study (as opposed to, for example, an animal study). Rather than specifying a fixed level of * The author is a Research Fellow at Harvard Medical School, a Postdoctoral Research Fellow in the Division of Pharmacoepidemiology and Pharmacoeconomics (Program On Regulation, Therapeutics And Law (PORTAL)) at Brigham and Women’s Hospital, and a member of the law faculty at Bentley University. S.J.D., Harvard Law School; J.D., Duke University; LL.M., Harvard Law School (waived); M.B.A., Boston College. The author wishes to thank William Fisher, Benjamin Roin, Aaron Kesselheim, Donald Light, Tyler Black, and the editors of the Washington and Lee Law Review for their helpful contributions. Any errors remain the author’s own. efficacy or even a flexible standard of efficacy that a drug must possess, the U.S. drug approval framework thus fully delegates to drug companies and to the free market the determination of what level of efficacy is acceptable. The critical implication is that the public (and physicians and insurers) should not rely on the fact of FDA approval as an indication that medicines, including new and very highly priced ones, possess efficacy that is meaningfully greater than no efficacy at all. Table of Contents I. Introduction David Kessler, a former Commissioner of the U.S. Food and Drug Administration (FDA), once boasted to Congress that the agency’s “rigorous demand for safety and efficacy . . . makes FDA approval the international gold standard.”1 If the U.S. drug approval system does indeed set the global efficacy benchmark, it is a cause for concern. Although the FDA deserves praise for its significant efforts in promoting safety and promptly approving new medicines, the agency operates under a legal efficacy standard that is as likely to engender disbelief as it is to incite indignation: 1. Testimony on FDA’s Role in Protecting and Promoting Public Health: Hearing Before the S. Comm. on Labor and Human Res., 104th Cong. (Feb. 21, 1996) (statement of David A. Kessler, Comm’r, Food and Drug Administration), available at http://www.hhs.gov/asl/testify/t960221a.html. Under U.S. law, there is no particular level of efficacy required for a new drug to be approved.2 Instead, drugs with near-zero efficacy can be approved, prescribed, and sold to patients who have real and sometimes very serious diseases or conditions.3 Patients and physicians would be right to consider this assertion skeptically. How could an ineffective drug be approved under a legal system where it is axiomatic that all new drugs must be proven “safe and effective”4 prior to government approval? This familiar and comforting rhetoric, however, conceals the illusory nature of what the underlying legal standard actually requires. The Federal Food, Drug, and Cosmetic Act5 requires only that there be “substantial evidence that the drug will have the effect it purports or is represented to have.”6 It is the thesis of this Article that this standard, along with the related concepts of gold standard testing, statistical significance, and clinical significance, do not prevent FDA approval of substantially ineffective remedies. The implications are alarming. Not only does an illusory efficacy standard create the possibility that many expensive drugs marketed today are essentially worthless, but the near-universal (but false) perception that FDA approval guarantees substantial effectiveness can lead physicians and patients to cede responsibility for critically evaluating drug value, thus adversely affecting treatment choices. While this harm must be balanced against the tremendous benefits flowing from FDA regulation, it nevertheless raises the specter that, in a significant sense, the stamp of “FDA approval” may actually work to harm public health. 2. See 21 U.S.C § 355(d) (2012) (stating that FDA Drug Approval guidelines require “substantial evidence” that “the drug will have the effect it purports or is represented to have”). 3. See Joan E. Shreffler, Bad Medicine: Good-Faith FDA Approval as a Recommended Bar to Punitive Damages in Pharmaceutical Products Liability Cases, 84 N.C. L. REV. 737, 758 (2006) (discussing how a grant of FDA approval only requires the benefits of a drug to outweigh foreseeable risks). 4. See, e.g., Pliva v. Mensing, 131 S. Ct. 2567, 2574 (2011) (noting that among the issues not in dispute was the fact that “[u]nder . . . the Federal Food, Drug and Cosmetic Act . . . a manufacturer seeking federal approval to market a new drug must prove that it is safe and effective”). 5. 21 U.S.C. § 301. 6. Id. § 355(d). II. The Illusory Legal Standard for Drug Efficacy The legal standard that is most closely related to the level of efficacy a new drug must possess in order to receive FDA approval is set forth in a lengthy section of Title 21 of the United States Code, the relevant portion of which states: If the Secretary finds . . . that . . . there is a lack of substantial evidence that the drug will have the effect it purports or is represented to have . . . or [the drug’s] labeling is false or misleading in any particular [then] he shall issue an order refusing to approve the [new drug] application.7 This language may sound as if it does not impose a requirement for any particular level of efficacy, and in fact it does not do so.8 The phrases “substantial evidence” and “the effect it purports or is represented to have” do impose efficacy-related requirements on drug sponsors.9 Neither, however, requires drugs to have anything more than next-to-zero levels of efficacy.10 What these two phrases require—and do not require—is discussed next. A. “The Effect It Purports or Is Represented to Have” Section 355(d), quoted above, does specify a level of efficacy that new drugs must have if they are to be approved. That level of efficacy is defined by statute to be whatever level the drug “purports or is represented to have.”11 In other words, rather than 10. Id. 7. Id. § 355(d) (emphasis added). 8. See DANIEL CARPENTER, REPUTATION AND POWER: ORGANIZATION IMAGE AND PHARMACEUTICAL REGULATION AT THE FDA 146, 156, 192–93 (2010) (describing efficacy as “a slippery concept,” “indefinable,” and “robustly ambiguous,” and discussing the absence of agreement or precision with respect to what was meant by “efficacy”). 9. See 21 U.S.C. § 355(d) (2012) (describing grounds for refusing application, approval of application, and substantial evidence). 11. Id. Strictly speaking, the term “efficacy” refers to the benefits a drug produces under ideal conditions, that is, under the controlled conditions of a clinical trial. In contrast, the term “effectiveness” refers to the benefits a drug produces under the usual circumstances of health care practice. See STEDMAN’S MEDICAL DICTIONARY (27th ed. 2000) (defining “efficacy” and “effectiveness”); STAN N. FINKELSTEIN & PETER TEMIN, REASONABLE RX: SOLVING THE DRUG PRICE CRISIS 9, 21 ( 2008 ) (noting similar definitions used by the European Union and specifying a fixed level of efficacy or a even a flexible standard of efficacy that a drug must possess, the statute fully delegates to drug companies the ability to specify any level of efficacy they desire.12 If clinical test results demonstrate that a drug’s efficacy that is only slightly above zero, that drug can nevertheless receive FDA approval so long as companies do not purport in the labeling that the drug is more effective than the evidence supports.13 The accompanying regulations merely repeat the statutory words verbatim, adding no additional requirement or clarification regarding efficacy level.14 As a result, the standard is almost entirely illusory because it leaves to the drug sponsor the ability to specify any non-zero level of efficacy.15 The real world result is predictable: Statements of efficacy contained in drug labels are often nearly meaningless, but are presented in such a way as to deemphasize the level of efficacy patients can expect while emphasizing the symptoms from which patients are seeking relief. For example, over-the-counter labeling for the analgesic Motrin (ibuprofen) states, innocently enough, that it “temporarily relieves minor aches and pains due to: headache . . . backache . . . muscular aches [and] toothaches . . . .”16 A patient who wants a headache to go away might mistakenly assume that by the International Network of Agencies for Health Technology Assessment, an international organization comprising agencies from twenty-nine countries); Hans-Georg Eichler et al., Relative Efficacy of Drugs: An Emerging Issue Between Regulatory Agencies and Third-Party Payers, 9 NATURE REVIEWS DRUG DISCOVERY 277, 279 box 1 (Apr. 2010) (same). However, because the terms are often used interchangeably or inconsistently with these definitions, the term “efficacy” will generally be used throughout this work for simplicity. 12. See 21 U.S.C. § 355(d) (2012) (discussing grounds for refusing applications and defining “substantial evidence”). 13. Id. 14. See 21 C.F.R. § 314.125(b)(5) ( 2009 ) (echoing the identical “substantial evidence” requirement found in federal statute). 15. Cf. Kenyon v. Jennings, 560 F. Supp. 878, 881 (D. Kan. 1983) (“An illusory promise is ‘a purported promise that actually promises nothing because it leaves to the speaker the choice of performance or nonperformance.’” (quoting BLACK'S LAW DICTIONARY 674 (5th ed. 1979))). 16. Drug Label for Motrin (ibuprofen), http://www.accessdata.fda.gov/drugs atfda_docs/label/2007/017463s105lbl.pdf (last visited Sept. 29, 2012) (on file with the Washington and Lee Law Review). ibuprofen can accomplish this result, at least temporarily, in light of the “temporar[y] relie[f]” promised in the label.17 Those who swallow two caplets of ibuprofen, however, are unlikely to experience either immediate or complete disappearance of pain. One double-blind, randomized and controlled trial, for example, found that of seventy-five patients who took all three of ibuprofen, acetaminophen or placebo at different times, eighteen preferred ibuprofen, eighteen acetaminophen, twelve placebo, and twenty-seven expressed no preference, which differences in preference were not statistically significant.18 Another randomized, blinded study assessed the intensity of headache on a four point scale (4 = intense; 3 = moderate; 2 = slight; 1 = none).19 Three hours after treatment, those taking ibuprofen reported scores of 2.05, while those taking placebo reported an average score of 2.48, a statistically significant but hardly impressive difference.20 The difference becomes even smaller (though still statistically significant) when one realizes that the baseline average scores for the two groups were different: 2.74 for those taking ibuprofen versus 2.98 for those taking placebo, yielding reductions in pain of 0.69 (2.74 minus 2.05) for ibuprofen versus 0.50 (2.98 minus 2.48) for placebo.21 A number of other studies reveal similarly unimpressive efficacy in relieving headache pain.22 The Motrin (ibuprofen) drug label, however, makes neither the claim that relief is immediate nor that it is complete.23 In fact, it promises no particular level of relief at all.24 Although Motrin is an over-the-counter drug, many prescription drugs also promise no particular level of relief. Among the top-selling prescription drugs in a recent year were Cymbalta (duloxetine), Plavix (clopidogrel), and Enbrel (etanercept).25 Cymbalta, a serotonin and norepinephrine reuptake inhibitor, is indicated for depression, anxiety, fibromyalgia, and musculoskeletal pain.26 A television commercial for Cymbalta emphasizes the symptoms of depression but, with respect to efficacy, notes only that “Cymbalta can help” and that “Cymbalta . . . treats many symptoms of depression.”27 The television commercial for Enbrel (etanercept) similarly states only that “Enbrel can help relieve pain, stiffness, and stop joint damage.”28 Small print briefly viewable during the advertisement states that “Enbrel was shown to be effective in 50% of psoriatic care.ahrq.gov/repFiles/AnalgesicsFinal.pdf (noting that several recent “goodquality systematic reviews” by the Cochrane Collaboration found no clear differences among nonselective NSAIDs in efficacy for treating knee, back, or hip pain). But see Bernard P. Schachtel & William R. Thoden, Onset of Action of Ibuprofen in the Treatment of Muscle-Contraction Headache, 28 HEADACHE: J. HEAD & FACE PAIN 471 (1988) (finding that ibuprofen provided substantially greater pain relief than placebo, but admitting that participating subjects were selected only if they reported previously satisfactory experience with nonprescription analgesics, i.e., participants may not have been representative subjects because they may have been unusually responsive to ibuprofen treatment). 23. Drug Label for Motrin (ibuprofen), supra note 16. 24. Id. 25. See Matthew Herper, The Best-Selling Drugs in America, FORBES (Apr. 19, 2011, 8:48 AM), www.forbes.com/sites/matthewherper/2011/04/19/the-bestselling-drugs-in-america (last visited Oct. 21, 2013) (listing the top-selling medicines in the United States in 2010) (on file with the Washington and Lee Law Review). arthritis patients at 6 months,” but this statement addresses only the fraction of people who experienced any relief, not the amount of relief experienced by those patients.29 Moreover, by implication the other half experienced no relief. A Plavix (clopidogrel) commercial boasts, as it changes ominous background music associated with symptoms to more uplifting music associated with the drug treatment, that “Plavix, in combination with aspirin and other heart medicines helps provide greater protection against heart attack or stroke than aspirin and other medicines alone.”30 The FDA has rebuked the maker of Plavix for overstating similar claims of efficacy in Plavix print advertisements.31 In each of these commercials, there is no claim to any particular level of efficacy.32 How much Cymbalta can “help” mitigate symptoms of depression, how much “Enbrel helps . . . stop joint damage” and how much Plavix “helps” protect against heart attack and stroke, are questions all conveniently left for the television viewer to imagine.33 The imagination, however, is not 29. Id. 31. See Letter from Andrew S.T. Haffer, U.S. Food & Drug Admin., to Kenneth Palmer, Sanofi Pharms. (May 9, 2001), http://www.fda. gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Enforcement ActivitiesbyFDA/WarningLettersandNoticeofViolationLetterstoPharmaceutical Companies/UCM166467.pdf (advising that a Plavix visual aid overstated and mislead viewers about the drug’s efficacy); see also Letter from Janet Norden, U.S. Food & Drug Admin., to Gregory M. Torre, Sanofi Pharms. (Dec. 18, 1998), http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformatio n/EnforcementActivitiesbyFDA/WarningLettersandNoticeofViolationLetterstoP harmaceuticalCompanies/UCM166391.pdf (“[C]laims that suggest Plavix has been ‘proven’ to be more effective than aspirin are misleading because they are not based on substantial evidence.”); Deepak L. Bhatt et al., Clopidogrel and Aspirin Versus Aspirin Alone for the Prevention of Atherothrombotic Events, 354(16) NEW ENG. J. MED. 1706, 1714 (2006) (“[T]he combination of clopidogrel plus aspirin was not significantly more effective than aspirin alone in reducing the rate of myocardial infarction, stroke, or death from cardiovascular causes . . . .”). 32. See supra notes 26–30 and accompanying text (asserting claims to help particular ailments but no degrees of aid). 33. The claim that “Enbrel can help relieve pain, stiffness, and stop joint damage” is particularly interesting because it is grammatically awkward. If an “and” were inserted between “pain” and “stiffness,” then the word “help” would modify only those two words. The use of the comma instead of “and,” by left entirely to chance. The music, imagery, prescription status, and fact of FDA approval, among other things, all help the viewer to imagine that the drug must be substantially effective, without ever stating this directly. Because the efficacy standard is a fully-adjustable hurdle, drugs that are able to jump that hurdle may be substantially ineffective, much as a five-year old can easily jump over a rope if that rope is lying on the ground. This is true not only for new drugs that are approved under the “purports or is represented to have” standard, but also for those approved prior to 1962, the year the standard was first introduced by the Kevauver-Harris Drug Amendments Act.34 After the 1962 Act was passed, the FDA Commissioner decided to retrospectively evaluate about 4,000 pre1962 drug formulations in what became known as the Drug Efficacy Study Implementation (DESI).35 DESI engaged thirty panels of experts who were asked to classify the drug claims as either (1) effective, (2) probably effective, (3) possibly effective, or (4) ineffective.36 It is often recognized that the large majority (81%) of drug claims subject to DESI review were classified in the latter three categories.37 That is, drugs approved between 1938 and 1962 could not be said to be unqualifiedly effective for (on average) four contrast, may be intended to make it sound as if “Enbrel can . . . stop joint damage” (a claim of 100% efficacy) when in reality the claim is only that “Enbrel can help . . . stop joint damage” (a claim of no particular level of efficacy). 34. Pub. L. No. 87-781, 76 Stat. 780 (1962) (codified at 21 U.S.C. § 301). 35. See NAT’L RESEARCH COUNCIL, DRUG EFFICACY STUDY: FINAL REPORT TO THE COMMISSIONER OF FOOD AND DRUGS, FOOD AND DRUG ADMINISTRATION 1 (1969) (describing the Commissioner’s decision to examine pre-1962 approved drugs still on the market). 36. Id. at 42–43. 37. See, e.g., Ralph F. Hall, Right Question, Wrong Answer: A Response to Professor Epstein and the “Permititis” Challenge, 94 MINN. L. REV. HEADNOTES 50, 70 (2010) (noting that only 19.1% of reviewed claims gained an “effective” rating); Matthew J. Seamon, Plan B for the FDA: A Need for a Third Class of Drug Regulation in the United States Involving a “Pharmacist-Only” Class of Drugs, 12 WM. & MARY J. WOMEN & L. 521, 541 n.172 (2006) (same); see also NAT’L RESEARCH COUNCIL, supra note 35, at 7. The 81% figure also included two additional rating categories, namely, “[e]ffective, but . . .” (i.e., where “much better safer or more conveniently administered drugs were . . . available”) and “[i]neffective as a fixed combination” (i.e., based on the principle that multiple drugs should not be administered when a single drug alone would be effective). Hall, supra, at 70. out of five claims, under the legal standard put in place in 1962.38 Less recognized in discussions of DESI is that even for those drugs that were placed into the most favorable category (“effective”), this categorization was based only on whether the drug could be said, based upon substantial evidence, to have “the effect [it] purports or is represented to have.”39 Under this standard, drugs could have received (and probably did receive) the top rating even if evidence showed them to perform only marginally better than nothing (i.e., placebo), so long as manufacturers did not claim that the drugs could do more than that. B. Substantial Evidence of Efficacy Versus Evidence of Substantial Efficacy The statutory language that most directly constitutes an efficacy standard is the requirement that a new drug have that level of efficacy that it “purports or is represented to have.”40 This is not the only language relating to efficacy, however. Earlier in the same sentence is the requirement that a new drug cannot be approved by the FDA unless there is “substantial evidence that the drug will have the effect it purports or is represented to have.”41 This quoted language might be shortened to a requirement that there be “substantial evidence [of efficacy].” Critically, the statute does not require “evidence of substantial efficacy.” Although a subtle distinction in word order, the statutory language makes clear something of great moment: it is not the efficacy of a drug that must be substantial in order to receive approval, but the evidence supporting that efficacy. Rather than require any minimum level of efficacy, the requirement of “substantial evidence” is merely an evidentiary standard, that is, it refers to the amount or sufficiency of evidence needed to support a conclusion. Like evidentiary standards in general, “substantial evidence” has no precise definition. In the spectrum of evidentiary standards, however, it is among the 38. See Hall, supra note 37, at 70–71 (recognizing the 81% statistic); Seamon, supra note 37, at 541 n.172 (same). 39. NAT’L RESEARCH COUNCIL, supra note 35, at 43. 40. 21 U.S.C. § 355(d) (2012). 41. Id. (emphasis added). easiest to satisfy. As construed by the Fourth Circuit, “substantial evidence requires more than a scintilla, but less than a preponderance, of the evidence.”42 This definition places the required sufficiency of evidence below not only a preponderance of the evidence (greater than 50% likelihood), but also far below “clear and convincing evidence” (greater than, perhaps, 80% likelihood) and toward the opposite end of the spectrum from “beyond a reasonable doubt” (perhaps, near 100%).43 It is therefore no wonder that New York’s highest court has described “substantial evidence” as “a minimal standard,”44 while a Delaware court described it as “the lowest standard of proof.”45 The Sixth Circuit has added that even “the possibility of drawing two inconsistent conclusions from the evidence does not prevent an administrative agency’s finding from being supported by substantial evidence.”46 43. There is a notable lack of consensus on exact percentages equivalents, other than the preponderance of the evidence standard, for which there is substantial but not universal agreement. See, e.g., United States v. Shonubi, 895 F. Supp. 460, 471 (E.D.N.Y. 1995) (“A survey of judges . . . found general agreement that ‘a preponderance of the evidence’ translates into 50+ percent probability. Eight judges estimated “clear and convincing” as between 60 and 70 percent probable . . . . Estimates for ‘beyond a reasonable doubt’ ranged from 76 to 90 percent, with 85 percent the modal response.”), vacated on other grounds, 103 F.3d 1085 (1997); Barbara D. Underwood, The Thumb on the Scales of Justice: Burdens of Persuasion in Criminal Cases, 86 YALE L.J. 1299, 1311 (1977) (“[A]lmost a third of the responding judges put ‘beyond a reasonable doubt’ at 100%, another third . . . at 90% or 95%, and most of the rest put it at 80% or 85%. For the preponderance standard, by contrast, over half put it at 55%, and most . . . put it between 60%, and 75%.”); Byron K. Warnken, Litigating “Forfeiture by Wrongdoing” After Crawford v. Washington, 41-AUG MD. B.J. 22, 24 ( 2008 ) (noting the “risk of factual error” to be “about 30 percent” under the clear and convincing evidence standard and “49 percent” under the preponderance of the evidence standard). 44. FMC Corp. v. Unmack, 699 N.E.2d 893, 896 (N.Y. 1998). 45. In re Susan S., No. 7764, 1996 WL 75343, at *12 (Del. Ch. Feb. 8, 1996) (citing Shipman v. Div. of Soc. Servs., 454 A.2d 767 (Del. Fam. Ct. 1982), aff'd, 460 A.2d 528 (Del. 1983)); see also Conn. Light & Power Co. v. Dep’t of Pub. Util. Control, 830 A.2d 1121, 1131 (Conn. 2003) (“Th[e] substantial evidence standard is highly deferential and permits less judicial scrutiny than a clearly erroneous or weight of the evidence standard of review.”) (quoting MacDermid, Inc. v. Dep’t of Envtl. Prot., 778 A.2d 7 (Conn. 2001)). 46. Painting Co. v. NLRB, 298 F.3d 492, 499 (6th Cir. 2002) (quoting NLRB v. Ky. May Coal Co., 89 F.3d 1235, 1241 (6th Cir. 1996)). The court also noted The Senate Report accompanying the 1962 Kefauver-Harris drug amendments clarifies what this standard means in the pharmaceutical context: “When a drug has been adequately tested by qualified experts and has been found to have the effect claimed for it, this claim should be permitted even though there may be preponderant evidence to the contrary based upon equally reliable studies.”47 The Senate Report, which is not itself law, is thus consistent with the general meaning of substantial evidence in that it will allow a claim to prevail even if the preponderance of the evidence indicates that it should fail. “Substantial evidence” is a “highly deferential standard” that is often used by courts when evaluating administrative agency decisions,48 allowing those decisions to stand even if the court would have reached a different conclusion based upon the same evidence. In the context of pharmaceuticals, the Senate Report explains that the deferential standard was intended to allow approval in “a situation in which a new drug has been studied in a limited number of hospitals and clinics and its effectiveness established only to the satisfaction of a few investigators qualified to use it,” or in other words, to ensure that minority viewpoints may be acted upon.49 The same statute that sets forth the substantial evidence requirement also elaborates with respect to its meaning,50 explaining that: The term “substantial evidence” means evidence consisting of adequate and well-controlled investigations, including clinical investigations, by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved, on the basis of which it could fairly and responsibly be concluded that “[t]he substantial evidence standard is a lower standard than [the] weight of the evidence [standard].” Id. at 499. 47. S. REP. NO. 87-1744 (1962), reprinted in 1962 U.S.C.C.A.N. 2884, 2892 (1962) (emphasis added). 48. Conn. Light & Power Co., 830 A.2d at 1131. 49. S. REP. NO. 87-1744 (1962), reprinted in 1962 U.S.C.C.A.N. 2884, 2892 (1962). The Senate Report also suggests that the substantial evidence standard may be important in allowing approval of drugs that help “a substantial percentage of the patients in a given disease condition but [that] will not be effective in other cases.” Id. 50. See 21 U.S.C. § 355(d) (2012) (limiting the definition by its terms to the efficacy portion of the new drug approval statute). by such experts that the drug will have the effect it purports or is represented to have . . . . 51 The usual substantial evidence standard is thus delineated more precisely in the context of drug approval to require “adequate and well controlled investigations, including clinical investigations . . . .”52 This phrase constitutes the basis for the requirement of clinical (i.e., human) trials. Moreover, because “adequate and well-controlled investigations”53 is in the plural form, it has been interpreted by the FDA to generally require at least two separate clinical trials,54 although the FDA will sometimes approve a new drug on the basis of a single study.55 The practice of approving a new drug on the basis of a single study, already a part of FDA practice, was codified by the FDA Modernization Act of 1997 (FDAMA),56 which added a provision explicitly empowering the Secretary of Health and Human Services57 to approve drugs on the basis of a single study under certain circumstances: If the Secretary determines, based on relevant science, that data from one adequate and well-controlled clinical investigation and confirmatory evidence (obtained prior to or after such investigation) are sufficient to establish effectiveness, 51. Id. (emphasis added). 52. Id. 53. Id. 54. See Warner-Lambert Co. v. Heckler, 787 F.2d 147, 151 (3d Cir. 1986) (“Because the Act uses the plural ‘investigations,’ the FDA requires drug manufacturers to submit at least two ‘adequate and well-controlled’ studies showing the effectiveness of the drug.”). 55. See U.S. FOOD & DRUG ADMIN., GUIDANCE FOR INDUSTRY: PROVIDING CLINICAL EVIDENCE OF EFFECTIVENESS FOR HUMAN DRUG AND BIOLOGICAL PRODUCTS 3 (1998) [hereinafter FDA GUIDANCE], http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformatio n/Guidances/UCM078749.pdf (describing scenarios when a single clinical study was approved); New Drug, Antibiotic, and Biological Drug Product Regulations; Accelerated Approval, 57 Fed. Reg. 58,942 (Dec. 11, 1992) (codified at 21 C.F.R. §§ 314 and 601) (noting the FDA’s existing practice of occasionally approving drugs on the basis of a single study “where the study was of excellent design [and] showed a high degree of statistical significance”). 56. Pub. L. No. 105-115, § 115(a), 111 Stat. 2296 (codified at 21 U.S.C. § 355(d)). 57. See 21 U.S.C. § 321(d) (2012) (defining “Secretary” to mean “Secretary of Health and Human Services”). the Secretary may consider such data and evidence to constitute substantial evidence for purposes of the preceding sentence.58 While approving a drug on the basis of a single study might be criticized as constituting a loosening of the standard, the more important concern is that even two trials will not ensure that new drugs possess substantial efficacy because the number of trials relates most directly only to the quantity of evidence rather than to any measure of efficacy level.59 Drug companies may spend $1 billion over a decade or longer to test a drug for effectiveness in order to satisfy the substantial evidence standard.60 This expense in both time and money, however, is primarily devoted not to increasing the efficacy of a drug nor even to ensuring that the drug’s efficacy meets some minimum threshold (unless “zero efficacy” is considered to be a threshold), but to proving to a reasonable certainty that there is any efficacy at all.61 C. The Concepts of Evidence and Efficacy Are Often Conflated The distinction between substantial evidence and substantial efficacy has not always been appreciated, even by those prominent in the field. David Kessler, for example, during his term as FDA Commissioner, expressed concern over a Congressional bill that would “explicitly lower the efficacy standard” in that it would allow a new drug to be approved based only on a single clinical trial rather than two clinical trials.62 As just discussed, the number of clinical trials relates to the evidence standard and not to any efficacy standard.63 Similarly, a New Jersey court noted that “[d]rugs approved between 1938 and 1962 were reevaluated [via DESI] to ensure compliance with the efficacy standard.”64 DESI, as discussed above,65 examined only the substantiality of the evidence of efficacy and did not seek to ensure that the drugs had any particular level of efficacy.66 The distinction between substantial evidence (what the standard is) and substantial efficacy (what the standard perhaps ought to be), is reminiscent of the classic distinction made by scientists—and often conflated by laypersons—between the term “precise” and the term “accurate.”67 Scientists traditionally use a dartboard analogy to illustrate the difference: if all darts land close to each other, but far from the bull’s eye of the dartboard, the darts have been thrown with precision, but they have not been thrown accurately.68 See Figure 1 below: Patients want drugs that reach reasonable efficacy targets, or, to use the language of the preceding analogy, a drug whose efficacy is accurate.70 What the legal standard requires, however, is a drug whose efficacy is precise.71 This is hardly a distinction that the average doctor likely considers on a daily basis, and is unlikely to be one that the average patient pauses to think about at all.72 Nevertheless, it is an important distinction to make in order to ensure that patients, physicians, and others are not misled into believing mistakenly that regulatory evidence standards ensure that only drugs with high levels of efficacy are approved.73 69. This is the classic bull’s-eye dartboard analogy depicting accuracy versus precision. 70. See supra notes 67–69 and accompanying text (illustrating the widely accepted “dartboard analogy”). 71. See SHAYNE COX GAD, CLINICAL TRIALS HANDBOOK 442 ( 2009 ) (noting that it is the confidence interval, and not the p-value per se, that is a measure of precision). 72. Physicians may be less informed about drug efficacy than is commonly believed. See FOOD AND DRUG ADMIN. & DIV. OF MED. SCIES. NAT’L RESEARCH COUNCIL, DRUG EFFICACY STUDY: FINAL REPORT TO THE COMMISSIONER OF FOOD AND DRUGS 65 (1969) [hereinafter DESI FINAL REPORT] (alluding to “prescribing doctors who were not in a position of knowledge” with respect to actual drug efficacy and were therefore heavily influenced by advertising); see also Ben Goldacre, What Doctors Don’t Know About the Drugs They Prescribe, TEDTALK (Apr. 5, 2013), http://www.huffingtonpost.com/ben-goldacre/prescriptiondrugs_b_3018272.html?icid=maing-grid7|main5|dl30|sec 1_lnk3%26pLid%3D295315 (last visited Oct. 21, 2013) (noting that physicians would be “misled” due to publication bias, even if they were to review the literature) (on file with the Washington and Lee Law Review). 73. If academic institutions were to operate under legal standards III. The Gold Standard and New Drug Approval The very term “gold standard” evokes feelings of confidence and certainty. As one dictionary defines it, the gold standard is “the best, most reliable, or most prestigious thing of its type.”74 Certainly, if one were measuring something as important as drug efficacy, it would be desirable to use such a pristine and highly regarded standard, and the relevant FDA regulations do not disappoint. These regulations incorporate, as a general matter, all of the essential elements normally considered to be part of the gold standard, as will be explained next.75 A. FDA Regulations Generally Define “Adequate and Well Controlled Investigations” According to the Gold Standard Although the term “gold standard” is not used anywhere in the federal statute or in the accompanying regulations, the section of the regulations entitled “adequate and well-controlled studies” sets forth the three elements generally understood to constitute the core of the gold standard for clinical trials: randomization, doubleblind administration, and placebo-control.76 analogous to those that bind the FDA, a student could pass a course with a failing grade so long as test results provided “substantial evidence”—to acceptable levels of certainty—that the student’s grasp of the course material was slightly above absolute incompetence. To extend the analogy, professors would then provide these marginal students with glowing letters of recommendation and insist that any future employer compensate them at exorbitant annual salaries. These annual salaries would be so high that in some cases they could only be paid with the help of government-regulated third parties who would provide at least partial reimbursement to the employers. If those third parties refused to pay, in light of the student’s (now graduate’s) test results, those third parties would be condemned as being cold and calculating, or even immoral. The analogy would be absurd and worthy of summary dismissal were it not so suggestive of what actually occurs with pharmaceuticals. 74. Gold Standard Definition, OXFORD DICTIONARIES, http://oxford dictionaries.com/definition/gold%2Bstandard?region=us (last visited Sept. 8, 2013) (on file with the Washington and Lee Law Review). 75. See 21 C.F.R. § 314.126 ( 2013 ) (containing the elements of the scientific gold standard: randomization, double-blind administration, and placebo control). For an explanation of the gold standard elements, see infra Part III.A. 76. See, e.g., FTC v. QT, Inc., 448 F. Supp. 2d 908, 938 (N.D. Ill. 2006) (“Dr. Feldstein agrees that a double-blind, placebo-controlled, randomized trial is the According to the regulations, “adequate and well-controlled studies,” more commonly known as clinical trials, must “us[e] a design that permits a valid comparison with a control to provide a quantitative assessment of drug effect.”77 That is, study participants taking the new drug must be compared to a scientific “control” group, which in its most basic form consists of patients taking an inactive placebo, the appearance of which is indistinguishable from the active treatment.78 The purpose of placebo control (combined with blinding, discussed below)79 is to address response bias, which is the tendency of study participants to respond because they believe they are being treated.80 The use of placebo thus helps to determine the extent of the effect caused by the chemical composition of the drug itself.81 Note that, although the regulations indicate that the drug effect should be assessable quantitatively, there is no minimum quantum of effect required.82 In other words, efficacy must be measured, but it need not be measured against any standard (other than zero). Researchers in clinical trials must ensure more generally that “[a]dequate measures are taken to minimize bias on the part of the subjects, observers, and analysts of the data.”83 The most common means for avoiding bias, and the one specifically “important.” In statistical usage, “significant” means “signifying a characteristic of the population from which the sample is drawn,” regardless of whether the characteristic is important.212 This double entendre can be skillfully employed to a drug company’s advantage. For example, Pfizer boasts on one consumeroriented website that “[i]n clinical studies, for patients with RA [rheumatoid arthritis], CELEBREX demonstrated significant reduction in joint tenderness/pain and joint swelling.”213 Similarly, Amgen proudly states in the headline to an online press release that Enbrel (etanercept) “[s]ignificantly [r]educed [l]evels of C[r]eactive [p]rotein.”214 Notwithstanding that it is probably not at all clear to the lay reader why it is beneficial for a patient to achieve lower levels of C-reactive protein, these promotional materials seem intended to convey the message that the drugs are not only beneficial, but beneficial enough to justify a trip to the doctor for a prescription and perhaps also an out-of-pocket copayment. That the drugs offer “significant” benefits may be true in the statistical sense, but lay readers not trained in statistics may perceive the message quite differently. Even if a claim of significance is true according to one of its meanings, courts have the power to deem that claim to be in violation of the Lanham Act215 “by necessary implication if it is 212. STEPHEN THOMAS ZILIAK & DIERDRE N. MCCLOSKEY, THE CULT OF STATISTICAL SIGNIFICANCE 110 ( 2008 ) (quoting W. ALLEN WALLIS & HARRY ROBERTS, STATISTICS: A NEW APPROACH 385 (1956)); see also Michael D. Maltz, Deviating from the Mean: The Declining Significance of Significance, 31 J. RES. CRIME & DELINQUENCY 434, 440 (1994) (“Statistical significance does not imply substantive significance, and most researchers know this—but this does not stop them from implying that it does.”). 213. About Celebrex, PFIZER ( 2013 ), http://www.celebrex.com/aboutcelecrex.aspx (last visited Sept. 17, 2013) (emphasis added) (on file with the Washington and Lee Law Review); see also Symbicort “Fishing” Commercial (2012), http://www.youtube.com/watch?v=oG9MxLwnapE (last visited Sept. 17, 2013) (“[Symbicort] significantly improved my lung function starting within five minutes.”) (on file with the Washington and Lee Law Review). 214. Sonia Fiorenza et al., New Findings Show Enbrel(R) (etanercept) Significantly Reduced Levels of C-Reactive Protein, a Marker of Inflammation, in Patients with Moderate to Severe Plaque Psoriasis, AMGEN (Feb. 1, 2008), http://www.amgen.com/media/media_pr_detail.jsp?releaseID=1103148 (last visited Oct. 22, 2013) (on file with the Washington and Lee Law Review). 215. See Pub. L. No.79-489, § 43, 60 Stat. 427 (1946) (codified as amended at 15 U.S.C. § 1125(a) ( 2013 ) (discussing civil actions for false designations of origin, false descriptions, and dilution). susceptible to more than one interpretation” and the other interpretation is false.216 In addition, the FDA has general authority to censure companies that disseminate advertisements that are misleading, including those that “[u]s[e] the concept of ‘statistical significance’ to support a claim that has not been demonstrated to have clinical significance or validity.”217 However, neither of these avenues of redress has been particularly powerful in policing the misuse of the concept of statistical significance. The Lanham Act, the principal federal trademark statute, is generally invoked by competitors seeking to use the necessary implication doctrine to enjoin another competitor’s advertisements, as in the Pepcid Complete case described above.218 Comparative advertisements, however, seem to be more pronounced in the over-the-counter (OTC) market, perhaps because advertised prescription drugs rely primarily on patent status to ward off competitors, while OTC products focus more on branding.219 Whatever the reason, there are few reported opinions that invoke the Lanham Act to combat the misuse of claims of statistically significant efficacy differences in the prescription drugs sector. FDA efforts are also unlikely to be adequate. Due to funding constraints, the FDA like all enforcement agencies must prioritize its efforts.220 As a result, low priority may be assigned to 216. SmithKline Beecham Consumer Healthcare, L.P. v. Johnson & Johnson-Merck Consumer Pharms. Co., 906 F. Supp. 178, 184 (S.D.N.Y. 1995) (citing Cuisinarts, Inc. v. Robot-Coupe Int’l Corp., No. 81 Civ. 731-CSH, 1982 WL 121559, at *1 (S.D.N.Y. June 9, 1982)). 217. 21 C.F.R. § 202.1(e)(7) ( 2013 ); see also id. § 202.1(e)(6)(vii) (stating that an advertisement is false or misleading if it “[c]ontains favorable data or conclusions from nonclinical studies of a drug, such as in laboratory animals or in vitro, in a way that suggests they have clinical significance when in fact no such clinical significance has been demonstrated”); 21 U.S.C. § 353b (2012) (“Prereview of Television Advertisements”); cf. 21 C.F.R. § 201.200 ( 2013 ) (“Disclosure of drug efficacy study evaluations [DESI] in labeling and advertising.”). 218. See SmithKline Beecham, 906 F. Supp. at 184 (S.D.N.Y. 1995) (applying the necessary implication doctrine). 219. See Simon P. Andersen & Regis Renault, Comparative Advertising: Disclosing Horizontal Match Information, 40 RAND J. OF ECON. 558, 577 ( 2009 ) (discussing why over-the-counter drugs such as Tylenol engage in comparative advertising to fend off competition). 220. See Bryan A. Liang, Fade to Black: Importation and Counterfeit Drugs, 32 AM. J.L. & MED. 279, 300 (2006) (“[T]he FDA is chronically underfunded, enforcement activities directed against claims of “significance” that, while literally true according to one meaning of the term, are less so under another. Bringing the FDA’s modest enforcement resources to bear against the massive advertising campaigns of powerful industries can be, as the FDA itself has complained, “like bringing a butter knife to a gun fight.”221 Given the volume of advertisements disseminated during prime-time television alone, thirty-one warning letters in a single year may indicate the extent of the problem rather than stand as an assurance that all misleading claims are dealt with swiftly.222 If prescription drug advertisements are misleading and current avenues of redress are inadequate, one possible solution is to legislatively ban such advertisements altogether. While this may seem an extreme step, almost every country to consider the issue has concluded that prohibiting or severely restricting direct-to-consumer prescription drug advertisements is appropriate. Only the United States and New Zealand (which has a population less than that of greater Atlanta)223 have concluded otherwise,224 and in the United States the decision to liberalize advertising came only in 1997.225 In response, leading to situations in which scarce resources must be stretched and policies prioritized for enforcement. . . .”). 221. R.J. Reynolds Tobacco Co. v. Food & Drug Admin., 696 F.3d 1205, 1221 (D.C. Cir. 2012). 222. See Jacqueline West, National Marketing Gone Unintentionally Global: Direct-To-Consumer Advertising of Pharmaceutical Products and the Internet, 10 J. INT’L BUS. & L. 405, 414 (2012), http://law.hofstra.edu/pdf/academics/ journals/jibl/jibl_volxii_national_marketing_gone_unintentionally_global_west.p df (stating that thirty-one warning letters were sent in 2011 by the Office of Prescription Drug Promotion). 223. See U.S. CENSUS BUREAU, STATISTICAL ABSTRACT OF THE UNITED STATES: 2012 (2012), http://www.census.gov/compendia/statab/2012/tables/12s0020.pdf (indicating an Atlanta area population of 5,269,000); Population Clock, STATISTICS NEW ZEALAND, http://www.stats.govt.nz/tools_and_services/ population_clock.aspx (last visited Sept. 17, 2013) (indicating an estimated New Zealand resident population of 4,458,047) (on file with the Washington and Lee Law Review). 224. See Marjorie Delbaere, Metaphors and Myths in Pharmaceutical Advertising, 82 SOC. SCI. & MED. 21, 21 ( 2013 ) (stating that, of the countries that have addressed the issue, only the United States and New Zealand permit direct to consumer advertisements for pharmaceuticals). 225. See Draft Guidance for Industry: Consumer-Directed Broadcast Advertisements, 62 Fed. Reg. 43,171–72 (Aug. 12, 1997) (discussing the FDA’s requirements for consumer-directed broadcasting); Lars Noah, Advertising state226 and federal227 bills have emerged advertising, and academics have argued the prohibition.228 to limit such merits of ad Given the serious public health issues at stake combined with the fact that very few advertised drugs offer significant therapeutic advantages over other drugs that may be much cheaper but unadvertised,229 a prohibition on drug advertising might well be preferable to the status quo. The suppression of misleadingly optimistic presentations of minimally advantageous new drugs might among other things prevent the crowding out of more balanced, healthy and realistic views of drug efficacy.230 It would Prescription Drugs to Consumers: Assessing the Regulatory and Liability Issues, 32 GA. L. REV. 141, 141 (1997) (noting the dramatic marketing shift toward direct-to-consumer prescription drug advertising during the fifteen years prior to 1997). 226. See, e.g., H.B. 2061, 188th Gen. Ct. (Mass. 2013) (“An Act Prohibiting Advertising by Pharmaceutical Companies”); H.B. 2646, 188th Gen. Ct. (Mass. 2013) (“An Act to Eliminate the Tax Deduction for Direct to Consumer Pharmaceutical Marketing”); H.C.R. 66, 2003 Leg., Reg. Sess. (Ky. 2003), available at http://www.lrc.state.ky.us/record/ 03rs/HC66/bill.doc (proposing a resolution “to limit, ban, or otherwise impose strict standards on direct-toconsumer advertising of drugs by pharmaceutical companies”). 227. See, e.g., H.R. 722, 112th Cong. (2011) (proposing the “Say No to Drug Ads Act,” which would “deny any [tax] deduction for direct-to-consumer advertisements of prescription drugs”); H.R. 2966, 111th Cong. ( 2009 ) (“Say No to Drug Ads Act”); H.R. 5105, 107th Cong. (2002) (“Say No to Drug Ads Act”). 228. See Kurt C. Stange, Time to Ban Direct to Consumer Prescription Drug Marketing, 5 ANNALS FAM. MED. 101, 102 (2007) (arguing that direct-toconsumer advertisements should be banned for prescription drugs); Joel Lexchin & Barbara Mintzes, Direct-to-Consumer Advertising of Prescription Drugs: The Evidence Says No, 21(2) J. PUB. POL’Y & MARKETING 194, 196–97 (2002) (providing evidence that direct-to-consumer advertising should not be used for prescription drugs). 229. See Lexchin & Mintzes, supra note 228, at 194 (“There is no evidence that direct-to-consumer advertising results in any improvement in health outcomes.”). 230. See George Loewenstein, Out of Control: Visceral Influences on Behaviour, 65 ORG. BEHAV. & HUM. DECISION PROCESSES 272, 272 ( 1996 ) (“[V]isceral factors have a disproportionate effect on behavior and tend to ‘crowd out’ virtually all goals . . . .”); cf. Catherine MacKinnon, Pornography, Civil Rights, and Speech, 20 HARV. C.R.-C.L. L. REV. 1, 18 (1985) (asserting that pornography “is not imagery in some relation to a reality . . . [but] is a sexual reality”). Analogously, television advertisements can create a false imagery of drug efficacy that becomes a perceived reality, leading patients to demand nearly worthless drugs no matter the cost or potential side effects. also help to rein in wasteful expenditures that needlessly inflate healthcare costs. Nevertheless, preventing businesses from communicating with their customers is a drastic step. From the business perspective, it can raise First Amendment concerns,231 while from the consumer’s perspective, it can block off a potential channel of useful information232 (even if little useful information is currently flowing through that channel). Most importantly, a less restrictive means of reforming direct-to-consumer advertising is available, namely, increasing the utility of the information in advertisements by requiring a clear presentation of efficacy data.233 Such a tempered approach would preserve channels of communication, increase transparency, leave the decision in the hands of consumers (and their doctors), and embody free market ideals that have been the traditional underpinning of the United States economic system.234 Should the reform prove insufficient within a reasonable period of time, prohibition could always be instituted as a last resort. 231. See Mark I. Schwartz, To Ban or Not to Ban—That Is the Question: The Constitutionality of a Moratorium on Consumer Drug Advertising, 63 FOOD & DRUG L.J. 1, 3 n.5 ( 2008 ) (noting that legislation proposed in 2007 that would have allowed the FDA to impose a moratorium on advertising was abandoned following claims that it would violate the First Amendment); see also Thompson v. W. States Med. Ctr., 535 U.S. 357, 374 (2002) (“We have previously rejected the notion that the Government has an interest in preventing the dissemination of truthful commercial information in order to prevent members of the public from making bad decisions with the information.”); Gerald Masoudi & Christopher Pruitt, The Food and Drug Administration v. The First Amendment: A Survey of Recent FDA Enforcement, 21 HEALTH MATRIX 111, 112 (2011) (noting that the FDA’s “curtailment of constitutionally protected commercial speech” can “remov[e] truthful (and useful) product communications from the marketplace”). 232. See generally Anthony D. Cox & Dena Cox, A Defense of Direct-toConsumer Prescription Drug Advertising, 53 BUS. HORIZONS 221 (2010) (acknowledging problems, but concluding that advertising can increase consumer knowledge and awareness). Cox and Cox also argue that direct-toconsumer advertising, despite its problems, is at least better than physician targeted promotion, which should be a greater source of public concern. Id. at 227. 233. Other proposals that fall short of a full ban have also been suggested. See, e.g., Margaret Gilhooley, Commercial Speech, Drugs, Promotion and a Tailored Advertisement Moratorium, 21 HEALTH MATRIX 97, 98–99 (2011) (discussing a prohibition on advertisements for only recently approved drugs, or alternately, for only the most high-risk recently approved drugs). 234. See City of Lafayette v. La. Power & Light Co., 435 U.S. 389, 416 (1978) (acknowledging “the Nation’s free-market goals”). 3. Statistical Significance Is a De Minimis Requirement that Can Be Met by Diet, Exercise, and Other Mundane, Inexpensive Treatments The low bar imposed by the statistical significance requirement might well allow for a number of mundane, inexpensive treatments to receive FDA approval, so long as they could qualify under the statutory definitions of a “drug” (or “device”).235 For example, clinical trials have demonstrated that the drug Aricept (donepezil) is statistically significantly more effective than a placebo in treating Alzheimer’s disease, and as a result the drug was approved by the FDA.236 But fruit juice, exercise, music, and even coffee might also be able to meet the lax significance standard. One study, for example, followed almost 2,000 people for seven years and concluded that fruit and vegetable juices were “highly significant” in delaying the onset of Alzheimer’s,237 suggesting what may be in any event a sensible dietary change to improve health. A meta-analysis of multiple studies concluded that exercise has a “robust and beneficial influence on the cognition of sedentary older adults,”238 while another meta-analysis concluded that music therapy was an effective treatment for Alzheimer’s.239 Research 235. See 21 U.S.C. §§ 321(g)(1), (h), (p) (2012) (defining the terms “drug,” “new drug,” and “device”). 236. See S.L. Rogers et al., A 24-Week, Double-Blind, Placebo-Controlled Trial of Donepezil in Patients with Alzheimer’s Disease, 50 NEUROLOGY 137, 137 (1998), http://www.stvincents.ie/dynamic/File/Donepezil%20study.pdf (describing how donepezil is more effective than a placebo in treating Alzheimer’s disease). 237. See Qi Dai et al., Fruit and Vegetable Juice and Alzheimer’s Disease: The Kame Project, 199 AM. J. MED. 751, 751 (2006) (discussing how fruit and vegetable juices play an important role in delaying the onset of Alzheimer’s disease, particularly among those who are at high risk for the disease). 238. Stanley Colcombe & Arthur F. Kramer, Fitness Effects on the Cognitive Function of Older Adults: a Meta-Analytic Study, 14 PSYCH. SCI. 125, 128 (2003); see also Patricia Heyn et al., The Effects of Exercise Training on Elderly Persons with Cognitive Impairment and Dementia: A Meta-Analysis, 85 ARCHIVES PHYSICAL MED. & REHABIL. 1694, 1694 (2006) (“Exercise training increases fitness, physical function, cognitive function, and positive behavior in people with dementia and related cognitive impairments.”). 239. See Susan M. Kroger et al., Is Music Therapy an Effective Intervention for Dementia? A Meta-Analytic Review of the Literature, 36 J. MUSIC THERAPY 2, 2 (1999) (finding the effect of music therapy to be “highly significant” for individuals with dementias). has also shown that caffeine is effective in treating Alzheimer’s Disease.240 Although diet, exercise, music, or caffeine may not necessarily be substantially effective in treating Alzheimer’s, the likelihood that these ordinary, inexpensive and easily available treatments could meet the statistical significance standard casts light on just how de minimis that standard is. It is perhaps no surprise that studies confirm the efficacy of diet and exercise in improving cognition.241 Nor is it surprising that caffeine, a stimulant, stimulates brain activity in some manner, or that music, which is self-evidently associated with emotion, can favorably affect the brain.242 These studies merely corroborate the conventional wisdom and lend a measure of scientific credibility to what the public thought it already knew. Few people, however, place their hopes for relief from Alzheimer’s in walking, listening to music, drinking coffee, or eating vegetables, and fewer still would be willing to pay $100 for a glass of vegetable juice or a 10-minute walk. Yet desperate patients will pay this much and more for an FDA-approved pill that may do as little, or less, than any of these ordinary treatments. The vulnerability of the statistical significance standard, therefore, is that it utterly fails to differentiate between factors that have a statistically significant effect in treating diseases or conditions, and those that are substantially effective in treating them. To offer yet another example, one randomized controlled trial concluded that “light therapy and fluoxetine [Prozac] are comparably effective treatments for patients with [seasonal affective disorder],” a type of depression.243 If this approximate equivalence were understood either by the medical community or the marketplace, it would be difficult to explain the $21 billion spent on Prozac during its first thirteen years on the market.244 One could instead simply buy very bright lights, move one’s workspace closer to a window, step outside during daylight hours, etc. V. “Clinical Significance” Does Not Imply Greater Efficacy Proponents of the current efficacy standard sometimes argue that drugs cannot be approved unless the level of efficacy is “clinically significant,” apparently suggesting that “clinical significance” requires an elevated degree of efficacy.245 There is no statutory or regulatory basis for such a distinction, nor can such a distinction be found in FDA guidance documents or court decisions. If clinical significance has any meaning distinct from statistical significance, it is that clinical significance means statistical significance in humans (as opposed to in animals or in vitro). A. The Law Requires Clinical Significance FDA regulations do include a clinical significance requirement in a number of provisions.246 For example, “effectiveness” in the context of over-the-counter products is defined as “a reasonable expectation that, in a significant proportion of the target population, the pharmacological effect of the drug, when used under adequate directions for use and warnings against unsafe alReport.pdf. 244. Bethany McLean, A Bitter Pill, FORTUNE, Aug. 13, 2001, at 118. 245. See, e.g., DAVID MACHIN, YIN BUN CHEUNG & MAHESH K.B. PARMAR, SURVIVAL ANALYSIS: A PRACTICAL APPROACH 1, 17 (2d. 1995), available at http://onlinelibrary.wiley.com.ezp-prod1.hul.harvard.edu/doi/10.1002/047003457 2.ch1/pdf (arguing that clinical significance, as opposed to statistical significance, implies a difference in efficacy between two treatments that is “substantial”); MICHAL J. CAMPBELL, DAVID MACHIN & STEPHEN J. WALTERS, MEDICAL STATISTICS: A TEXTBOOK FOR THE HEALTH SCIENCES 1, 288 (4d. 2010), http://tinyurl.com/lal6sb3 (arguing that results can be statistically but not clinically significant). 246. Infra notes 247–49 and accompanying text. use, will provide clinically significant relief of the type claimed.”247 Parallel provisions require that biologics “serve a clinically significant function in the diagnosis, cure, mitigation, treatment, or prevention of disease in man,”248 and that medical devices “provide clinically significant results.”249 With respect to the efficacy needed for new prescription drug approval, the term “clinically significant” appears nowhere in the statute250 or regulations,251 but the statute does require the undertaking of “clinical trials” that “form the primary basis of an effectiveness claim.”252 Thus, the clinical significance requirement is incorporated into the new drug statute as well as applying in other areas of FDA regulation. B. Clinical Significance Means Statistical Significance in Humans Although the law requires clinical significance in a variety of contexts,253 nowhere in the regulations or statute is it stated that a showing of clinical significance for new drugs necessitates an elevated degree of efficacy vis-à-vis statistical significance. Instead the most plausible reading of the law is that clinical significance 247. 21 C.F.R. § 330.10(a)(4)(ii) ( 2013 ) (emphasis added). 248. Id. § 601.25(d)(2) (emphasis added). 249. Id. § 860.7(e)(1) (emphasis added). 250. See 21 U.S.C. § 355 (d)(7) (2012) (defining substantial evidence to include “evidence consisting of adequate and well-controlled investigations, including clinical investigations”). 251. See, e.g., 21 C.F.R. § 201.57(a)(7) ( 2013 ) (noting that “clinically significant clinical pharmacologic information” must appear in the “[h]ighlights of prescribing information” section of drug labeling); id. § 201.57(c)(3)(i)(J) (requiring drug labeling to indicate “[e]fficacious . . . concentration ranges . . . if established and clinically significant”); see also Karen M. Becker et al., Scientific Dispute Resolution: First Use of Provision 404 of the Food and Drug Administration Modernization Act of 1997, 58 FOOD & DRUG L.J. 211, 220 (2003) (noting that in one case where clinical significance was specifically at issue, the FDA “shifted the scientific dispute from a complex specific question focused on clinical significance . . . to any scientific issue that . . . provided a basis for its not-approvable decision”); cf. 21 C.F.R. § 860.7(e)(1) (requiring reasonable assurance that medical devices provide clinically significant results). 252. 21 U.S.C. § 355(b)(5)(B) (2012). 253. Supra Part V.A. merely requires statistical significance in human trials, as opposed to animal trials or in vitro studies.254 This distinction is made explicitly in section 202.1 of the FDA drug advertising regulations, which provide that “as used in this section, ‘clinical investigations,’ ‘clinical experience’ and ‘clinical significance’ mean in the case of drugs intended for administration to man, investigations, experience, or significance in humans.”255 Elsewhere in section 202.1, the regulation clarifies what does not constitute clinical significance, stating that an advertisement is false or misleading if it “contains favorable data or conclusions from nonclinical studies of a drug, such as in laboratory animals or in vitro, in a way that suggests they have clinical significance.”256 Another provision in the same section states that an advertisement may be false or misleading if it “[u]ses the concept of ‘statistical significance’ to support a claim that has not been demonstrated to have clinical significance or validity,” i.e., if it has not been demonstrated to have statistical significance in humans.257 Figure 5 reflects the function of the clinical significance standard. By the terms of the FDA drug advertising regulation, this definition of clinical significance as meaning statistical significance in humans applies only to section 202.1.258 Nevertheless other documents such as FDA guidance and government reports are not inconsistent with this definition.259 A Government Accountability Office report, for example, notes that although there is no definition of “clinical significance” in the FDA medical device regulations, in the context of medical devices, the term is 254. Infra text accompanying notes 256–64. 255. 21 C.F.R. § 202.1(e)(4)(ii)(b) ( 2013 ). 256. Id. § 202.1(e)(6)(vii) (emphasis added). 257. Id. § 202.1(e)(2)(7)(ii). 258. Id. § 202.1(e)(4)(ii)(b). 259. Infra notes 261–64 and accompanying text. understood to mean results that “have a positive effect on the disease being treated according to the standard of care for the related field.”260 An FDA guidance document explains how to “provid[e] clinical evidence of effectiveness for human drug and biological products,”261 which at no point indicates that clinical significance implies an elevated level of efficacy. Section 2 of the guidance document, for example, discusses quantity of evidence, while Section 3 discusses quality of evidence.262 Both sections explain at length the flexible nature of the evidence standard, noting that in some situations “effectiveness of a new use may be extrapolated entirely from existing efficacy studies” without the need to conduct an additional study,263 and that under other circumstances “it is possible for sponsors to rely on [certain] studies to support effectiveness claims, despite less than usual documentation or monitoring.”264 C. Cases Addressing Absolute Efficacy Fail to Distinguish Clinical and Statistical Significance The few cases to address both clinical and statistical significance fail to distinguish the terms on the basis of efficacy level. In general, they do not clearly distinguish the two terms at all, sometimes implying that there is a distinction but then declining to reach a decision on the basis of any distinction and often failing to clearly articulate or define any distinction.265 In 260. U.S. GOV’T ACCOUNTABILITY OFFICE, GAO-07-996, MEDICAL DEVICES: FDA’S APPROVAL OF FOUR TEMPOROMANDIBULAR JOINT IMPLANTS 8 n.9 (2007), http://www.gao.gov/new.items/d07996.pdf. 261. FDA GUIDANCE, supra note 55, at 1 n.1. 262. See id. at 6–16 (providing guidance on the quantity of evidence needed in particular circumstances to establish substantial evidence of effectiveness); id. at 16–20 (discussing the factors that influence the quality of documentation evidence needed to support approval of a new human drug and biological product). 263. Id. at 6. 264. Id. at 17. 265. See infra notes 267–82 and accompanying text (discussing a case that addresses but fails to define a distinction between clinical and statistical significance). other cases, clinical significance has been treated as if it is essentially synonymous with statistical significance.266 One of the cases to discuss both clinical and statistical significance is the 1986 Third Circuit case of Warner-Lambert Co. v. Heckler,267 which involved the FDA’s withdrawal of approval of several oral proteolytic enzymes that had long been promoted as effective in relieving inflammation and pain, especially that arising from surgery, trauma, infection and allergic reactions.268 The drugs had initially received FDA approval prior to the Drug Amendments of 1962,269 at a time when approval formally required only a showing of safety, but not efficacy.270 The 1962 amendments required proof of efficacy not only for any new drugs submitted for approval after the effective date of the amendments, but also required the FDA to go back and review the efficacy of drugs that had already been approved prior to 1962, including the oral proteolytics at issue in Warner-Lambert.271 Following extensive review of the data submitted by Warner-Lambert and the other manufacturers in the case, an FDA administrative law judge (ALJ) concluded that the manufacturers had failed to establish that the drugs were effective.272 The FDA Commissioner upheld this finding.273 More than twenty years after the 1962 amendments, 266. See infra notes 282–87 and accompanying text (discussing two cases that did not distinguish between or base their holdings on a distinction between clinical and statistical significance). 267. 787 F.2d 147 (3d Cir. 1986). 268. See id. at 149 (“The Commissioner withdrew approval of the new drug applications for these drugs after concluding that there was a lack of substantial evidence that the OPEs will have effects they are purported or represented to have for their intended conditions of use.”). 269. Pub. L. No. 87-781, 76 Stat. 780 (1962) (codified in scattered sections of 21 U.S.C.). 270. See Warner-Lambert, 787 F.2d at 149 (“At the time approval was granted, the Food, Drug, and Cosmetic Act required the FDA to determine only that a drug was safe for human use.”). 271. See id. (“The 1962 amendments also required the FDA to reevaluate drugs that it had previously approved.”). 272. See id. at 150 (“The ALJ thus found that the drug manufacturers had not met their statutory burden of producing evidence demonstrating that the OPEs were effective.”). 273. See id. (“The Commissioner also found that there was a lack of substantial evidence that the . . . OPEs have the effects represented, and, accordingly, withdrew approval.”). the case finally reached the Third Circuit, which upheld the Commissioner’s findings.274 On the surface, certain statements in Warner-Lambert appear to support the proposition that statistical significance is distinctly different from clinical significance. According to the Third Circuit, “[t]he Commissioner's interpretation of the statute as requiring a showing of clinical significance, rather than merely statistical significance, is persuasive.”275 However, the rejection by the FDA (and court) for lack of efficacy seems in fact to have been based primarily on the faulty methodology of the studies under consideration rather than on any distinction between clinical and statistical significance.276 For example, one study had made 240 comparisons between the placebo and study groups, finding six of those comparisons to be statistically significant.277 However, as discussed above, at the level of statistical certainty usually required for drug approval (p=.05), one in twenty studies can be expected to reflect a Type I error, erroneously indicating efficacy where there is none.278 With 240 comparisons, this would suggest (assuming independence) that perhaps twelve comparisons might erroneously show statistical significance where none exists, which is in the neighborhood of what was in fact observed.279 More importantly, the FDA Commissioner had found that the post-hoc “stratification of the subjects into subgroups . . . had no scientific basis.”280 What this means in lay terms is that it appeared to the 274. See id. at 159–60 (finding that the Commissioner had a reasonable basis for disqualifying each submission of Warner-Lambert’s studies attempting to establish that the drugs were effective and noting that the rejection of the studies is consistent with the possibility that the OPEs do not work). 275. Warner-Lambert Co. v. Heckler, 787 F.2d 147, 155 (3d Cir. 1986). 276. See id. at 160 (discussing the Commissioner’s rejection of faulty studies). 277. See id. at 155 (discussing the results of the study on the therapeutic effect of OPE Chymoral). 278. See 44 Fed. Reg. 51512, 51520 col. 3 (Aug. 31, 1979) (“As a matter of scientific custom, a statistically significant difference has sometimes been considered one that is likely to occur by chance 1 in 20 times or less. . . .”). 279. See Warner-Lambert, 787 F.2d at 155 (“Of the 240 tests, only six provided statistical results indicating that Chymoral had some effectiveness . . . .”). 280. Id. at 155. The FDA has repeatedly urged caution when statistical significance is found after multiple comparisons are made, owing to the elevated risk of Type I errors. See, e.g., William B. Hood, More on Sulfinpyrazone After FDA that the manufacturers had inappropriately mined the data, after the fact, in such a way as to create the appearance of statistically significant results where none existed.281 In another Third Circuit case from the 1980s, United States v. 225 Cartons . . . of an Article or Drug,282 the court noted with approval the FDA’s requirement that new drugs demonstrate “a clinically, i.e., therapeutically, significant benefit . . . .”283 Once again, however, the drug product in question was not rejected on the basis of any distinction between clinical and statistical significance, but on the basis that the studies submitted by the manufacturer were inadequate to show that each of the putative active ingredients contributed to the drug’s efficacy.284 Nowhere did the court hold that statistically significant, but not clinically significant, results had been established. Similarly, in American Home Products Corp. v. Johnson & Johnson, Inc.,285 the Second Circuit found “no reliable evidence showing that [the aspirin in Anacin®] reduces inflammation to a clinically significant extent in the conditions listed in the Myocardial Infarction, 306(16) NEW ENG. J. MED. 988, 988–89 (1982) (discussing one study with inconsistent findings in which the FDA had concerns about data misclassification and exclusion). 281. See Warner-Lambert Co. v. Heckler, 787 F.2d 147, 155 (3d Cir. 1986) (showing that the six statistically significant results demonstrating effectiveness for reduction of pain were spread out over several different subgroups suffering various ailments and no comparison of the total drug group to the total placebo group was ever made). Repeated testing for statistical significance at frequent intervals during the trial process can also bias results and lead to Type I errors. See S.J. Pocock, Size of Cancer Clinical Trials and Stopping Rules, 38(6) BRIT. J. CANCER 757, 761 (1978) (“The more often one performs a significance test on the accumulating results in a trial, the greater is the chance that some significant difference will eventually be detected, even if the treatments are really equally effective.”); see also J.L. Haybittle, Repeated Assessment of Results in Clinical Trials of Cancer Treatment, 44 BRIT. J. RADIOLOGY 793, 796 (1971) (urging similar caution). 871 F.2d 409 (3d Cir. 1989). 283. Id. at 416. 284. See id. at 415 (following the district court’s ruling that “Sandoz had failed to produce such studies for its FWC combination products, and thus the court rejected its claim of general recognition” (citing United States v. 225 Cartons . . . of an Article or Drug, 687 F.Supp. 946, 962 (D.N.J. 1988)). Under the applicable FDA regulation, it must be shown that “each component [of a combination drug product] makes a contribution to the claimed effects.” Id. (quoting 21 C.F.R. § 300.50(a) (1988)). 285. 436 F. Supp. 785 (S.D.N.Y. 1977), aff’d, 577 F.2d 160 (2d Cir. 1978). advertisements at OTC [over-the-counter] dosages.” As in 225 Cartons, the Second Circuit based its holding not on any distinction between clinical and statistical significance, but on the basis of inadequate studies. The court noted that some of the documents submitted in support of efficacy consisted of “informal pieces” that were “not studies or tests at all.”286 Other documentation provided some evidence of statistically significant efficacy with respect to rheumatoid arthritis, but rheumatoid arthritis was not among the conditions for which the manufacturer was now claiming efficacy.287 A 1979 administrative decision by then-FDA Commissioner Donald Kennedy also appears at first to endorse a meaningful distinction between clinical and statistical significance.288 In a Final Decision following a formal evidentiary public hearing in an adjudicative proceeding for the cough suppressant Benylin (diphenhydramine), Kennedy emphatically rejected “the fallacy of equating statistical significance with clinical significance.”289 He dismissed a 9% reduction in coughing, stating that it “may be statistically significant . . . but is not clinically significant.”290 In the end, however, the decision to decline approval for the antitussant indication of Benylin (diphenhydramine) seems to have been based on a finding that neither of the two studies qualified as an “adequate and well controlled investigation[],” and that therefore there was a “lack of ‘substantial evidence’ . . . that Benelyn will have the effect it purports . . . to have.”291 The Commissioner found troubling (1) the fact that statistically significant results were obtained only on the first day of the study;292 (2) that those results were not strongly statistically 286. Id. at 800–01. 287. See id. at 799 (discussing the general acceptance that Anacin has an anti-inflammatory effect in the treatment of rheumatic diseases at dosages exceeding that recommended for over-the-counter use). 288. Infra notes 289–90 and accompanying text. 289. Benylin Final Decision, 44 Fed. Reg. 51,512, 51,521 col. 1 (Aug. 31, 1979). 290. Id. at 51,521 col. 2. 291. Id. at 51,537 col. 1. 292. See id. at 51,521 col. 3 (“It should also be noted that the results of the . . . study were statistically significant only on the first day of the study. . . .”). significant;293 (3) that overall more patients were satisfied with the placebo than with Benelyn (diphenhydramine);294 (4) that overall the physician-investigators did not rate Benelyn (diphenhydramine) differently from placebo with any statistical significance;295 (5) that the placebo controls were inadequate because they contained ingredients that may have had pharmacological activity;296 and (6) that the statistically significant results that were found were based on subjective responses (given by children aged six to twelve years) which the Commissioner found unreliable.297 In short, a number of factors other than any difference between statistical and clinical significance led to the Commissioner’s finding. In any event, the skeptical views of statistical significance expressed by a single FDA Commissioner who served in that role for only twenty-six months during the 1970s298 do not seem to have had a lasting impact on subsequent judicial decisions interpreting the substantial evidence standard, as seen in the cases just discussed.299 The lack of any meaningful and enduring distinction between clinical and statistical significance with respect to drug efficacy has not gone entirely unnoticed.300 One scholar, after exhaustively 293. See id. (“[T]he results even on [the first day] were just on the borderline of statistical significance. A change in the reports of just a few patients would have eliminated this significance.”). 294. See id. (“More patients were satisfied with the [placebo] (90.3 percent) than with Benylin (84.3 percent).”). 295. See id. (“The other such measure was a question directed to investigators, which called for an overall rating as to beneficial drugattributable results from medication. The results did not reveal any statistically significant differences between Benylin and the [placebo]. . . .”). 296. See id. at 51,527 col. 3 (“I find that ammonium chloride and sodium citrate in the amounts used in the [placebo] may have expectorant, demulcent, or other pharmacological activity.”). 297. See id. at 51,529–30 (describing the inability of the patients to provide “valid subjective evaluations”). 298. U.S. Food & Drug Admin., About FDA: Donald Kennedy, Ph.D. (Feb. 20, 2009), http://www.fda.gov/AboutFDA/WhatWeDo/History/Leaders/Commission ers/ucm093736.htm (last visited Sept. 18, 2013) (on file with the Washington and Lee Law Review). 299. See supra notes 267–87 and accompanying text (discussing judicial decisions interpreting the “substantial evidence” standard). 300. See infra note 301 and accompanying text (discussing an article that compares clinical and statistical significance). analyzing the meaning of clinical significance in the context of FDA approval, patent infringement, false advertising, and product liability cases, concluded: Having presented a survey of the various indications from case law, legislative materials, and academic sources, it is apparent how little clarity, and certainly how little consensus, there is concerning the meaning and appropriate usage of the phrase “clinical significance.” . . . In fact, it appears that these requirements [for clinical significance] are so much like those for finding statistical significance as to be simply redundant. . . . As the phrase stands now, it makes little if any positive contribution to drug-related litigation, while at the same time causing several important problems that will only grow worse . . . .301 Oddly, the distinction between clinical significance and statistical significance contained in the advertising regulations discussed above has been largely overlooked by the courts, commissioners and commentators that have discussed the subject.302 D. Cases Addressing Comparative Efficacy Fail to Distinguish Clinical and Statistical Significance Even in the context of the FDA drug advertising regulation,303 the meaning of clinical significance has sometimes been seemingly misunderstood. Section 202.1 defines as possibly false or misleading those advertisements that “[u]se[] the concept of ‘statistical significance’ to support a claim that has not been demonstrated to have clinical significance or validity.”304 Only two reported cases quote or cite this provision, and only one of these engages with it substantively.305 In that case, AstraZeneca had 301. Sarah M.R. Cravens, The Usage and Meaning of “Clinical Significance” in Drug-Related Litigation, 59 WASH. & LEE L. REV. 553, 594–96 (2002). 302. Similar language defining clinical significance has appeared in the drug advertising regulations since at least 1969. 21 C.F.R. § 1.105(e)(4)(iii)(b) (1969). 303. 21 C.F.R. § 202.1 ( 2013 ). 304. 21 C.F.R. § 202.1(e)(7)(ii). 305. See AstraZeneca LP v. TAP Pharm. Prods., Inc., 444 F. Supp. 2d 278, 282–89 (D. Del. 2006) (engaging in substantive discussion on 21 C.F.R. §202.1(e)(7)); Pa. Emps. Benefit Trust Fund v. Zeneca Inc., 499 F.3d 239, 248 (3d Cir. 2007) (mentioning 21 C.F.R. § 202.1(e)(7)), vacated, 129 U.S. 1578 ( 2009 ). promoted Nexium (esomeprazole) in a “Better is Better” campaign that claimed, among other things, that “recent medical studies . . . prove Nexium heals moderate to severe acid related damage in the esophagus better than the other leading prescription medicine.”306 One of the human studies put forth by AstraZeneca reported an overall healing rate of 92.6% for Nexium (esomeprazole) versus 88.8% for Prevacid (lansoprazole), an unimpressive difference that was nevertheless statistically significant.307 TAP Pharmaceuticals, the maker of Prevacid (lansoprazole), asserted that AstraZeneca had engaged in false advertising in violation of the Lanham Act,308 and cited in support the FDA drug advertising regulations that prohibit the misleading use of statistical significance to mean clinical significance.309 TAP argued that the advertisement was “literally false because Nexium is only marginally better at healing EE [erosive esophagitis], and that difference is clinically meaningless.”310 Elsewhere, TAP asserted that “the Castell and Fennerty studies [on humans], as well as other studies, while statistically significant, are not clinically significant.”311 Although the court declined to find a violation of the FDA drug advertising regulations, it did so without any reference to the distinction between animal and in vitro studies on the one hand, and clinical studies on the other.312 Indeed, the court seemed to tacitly accept the suggestion that clinical significance meant meaningful significance, finding that “the Castell and Fennerty studies are relevant to a consumer's use of Nexium” because “Nexium is at least statistically significantly better at healing 306. AstraZeneca LP, 444 F. Supp. 2d at 282. 307. Id. at 282–83. 308. Trademark Act of 1946, 15 U.S.C. §§ 1051–1072. 309. See AstraZeneca LP, 444 F. Supp. 2d at 295 (discussing TAP’s assertion that AstraZeneca had engaged in false advertising). 310. Id. at 282. 311. Id. at 289. 312. See id. at 295. Thus, citation to the FDA guidelines, in the absence of proof of literal falsity or misleading of the public, is insufficient to show that the claims in the Better is Better campaign are false. Because there are no genuine issues of material fact, and TAP cannot meet its burden on literal falsity, summary judgment will be granted to AstraZeneca on this issue. [esophageal] damage.”313 The court also pointed out that because of the “‘separate jurisprudence that has evolved’ under the Lanham Act and under the FDA,” the mere violation of the FDA drug advertising regulation in question, even if established, would be insufficient to show that the claims were literally false or misleading under the Lanham Act.314 TAP could not assert the FDA drug advertising regulations directly because, in general, only the United States may bring actions under the Food, Drug and Cosmetic Act315 or FDA drug advertising regulations.316 VI. Conclusion The very long and expensive process of new drug research and development might suggest to casual observers that the efficacy standard for drugs is elevated and substantial, but the review of the law just presented reveals that while the evidence standard may be substantial, the efficacy standard itself is almost entirely illusory. Under 21 U.S.C. § 355(d), drug sponsors may obtain FDA approval of a new drug so long as they do not “purport[] or . . . represent[]” the drug to have greater efficacy than can be shown by substantial evidence, essentially delegating to drug companies the ability to set as low an efficacy bar as they wish (safety aside). Moreover, the substantial evidence standard itself allows for approval of a new drug based upon two (in some cases, one) statistically significant clinical trials “even though there may be preponderant evidence to the contrary based upon equally reliable studies.”317 Not only do the trials that might constitute 313. Id. at 282. 314. Id. at 295 (quoting Sandoz Pharm. Corp. v. Richardson-Vicks, Inc., 902 F.2d 222, 229 (3d Cir. 1990)). 315. See 21 U.S.C. § 337(a) (2012) (“[A]ll such proceedings for the enforcement, or to restrain violations, of this chapter shall be by and in the name of the United States.”); State ex rel. McGraw v. Johnson & Johnson, 704 S.E.2d 677, 687 n.6 (W.Va. 2010) (“[T]ypically, only the United States is entitled to enforce an action under the FDCA. As such, claims brought to enforce violations of the FDCA by any party other than the United States are generally preempted.” (citation omitted)). 316. See Kemp v. Medtronic, Inc., 231 F.3d 216, 236 (6th Cir. 2000) (“[N]o private cause of action exists for a violation of the FDCA.”). 317. S. REP. NO. 87-1744 (1962), reprinted in 1962 U.S.C.C.A.N. 2884, 2892. “preponderant evidence to the contrary” not necessarily bar approval, but selective publication means that they often may not even be known to prescribing doctors, legislators, insurance companies and others, frustrating private efforts at rational drug use. Despite both legislative and private efforts to curb selective publication of only positive trials, publication bias remains a problem.318 The sensible elements that underlie the substantial evidence standard also fail to ensure that new drugs possess any particular level of efficacy. “Substantial evidence” is defined by statute to mean “evidence consisting of adequate and well-controlled investigations, including clinical investigations.”319 Accompanying FDA regulations suggest, but do not necessarily require, that these investigations conform to the “gold standard.” The gold standard elements of randomization, blinding, and placebo control may help to counter the various types of bias in the experimental process, but none specifies the magnitude of efficacy needed for a trial to succeed. Similarly, the concept of statistical significance, which is generally used by the FDA in its evaluations of efficacy based on gold standard trials, is merely a measure of certainty and not a measure of efficacy. “Clinical significance” and “statistical significance” are distinct concepts, and the law does require that new drugs demonstrate evidence of clinical significance, but the term “clinical significance” merely means significance in humans as opposed to significance in vitro or in non-human animals. The difference in these two terms thus lies not in the magnitude of efficacy, but in the nature of the trial. Figure 6 summarizes the various challenges in evaluating drug efficacy and the regulatory or scientific standards designed to address each: 318. See supra Part IV.A.3 and Figure 3 (discussing publication bias). 319. 21 U.S.C. § 355 (d)(7) (2012). Nature of Problem Figure 6: Efficacy Evaluation Problems and Existing Regulatory Solutions Problem Efficacy data may not be relevant to humans Biases, e.g., • Selection bias • Observer bias • Response bias Anecdotal or unreliable evidence or testimonials Type I error, (i.e., the appearance of efficacy is actually due to random variation) Selective publication Magnitude Efficacy level is too low Clinical significance Gold standard • Randomization • Blinding • Placebo control Substantial evidence standard Statistical significance standard None (i.e., allow the “free-market” to evaluate the effect a drug “purports or is represented to have”) In short, there is no legal efficacy standard. Although the need for statistical significance might imply that new drugs must at least be better than nothing (zero efficacy), there is no minimum quantum of difference from zero that is required, making the standard illusory in a way reminiscent of how mathematics describes .9¯ (point nine repeating) as exactly equal to 1. The influencing of trial results by drug sponsors, suggested by studies that demonstrate inconsistent comparative efficacy results that correlate with the study sponsor, can make whatever tiny quantum of efficacy difference that may be required entirely disappear. Making highly effective drugs may be complex, expensive, and difficult, and the law must be sensitive to the significant technical challenges drug companies face. At the same time, greater awareness of the illusory efficacy standard is badly needed in order to enable physicians, patients, governments, and society at large to make rational choices about the risks they are II. The Illusory Legal Standard for Drug Efficacy.............. 2077 A. “The Effect It Purports or Is Represented to Have”. ..................................................................... 2077 B. Substantial Evidence of Efficacy Versus Evidence of Substantial Efficacy .............................. 2083 C. The Concepts of Evidence and Efficacy Are Often Conflated .................................................. 2087 III. The Gold Standard and New Drug Approval ................. 2090 A. FDA Regulations Generally Define “Adequate and Well-Controlled Investigations” According to the Gold Standard ................................................. 2090 B. FDA Regulations Do Not Necessarily Require the Gold Standard ..................................................... 2093 IV. The Gold Standard Does Not Ensure Substantial Efficacy ............................................................................. 2095 A. The Gold Standard Does Not Prevent the Undertaking of Multiple Trials ................................ 2096 1. Using Multiple Trials to Obtain Drug Approval: The Antidepressants .......................... 2098 2. The Larger Phenomenon: Publication Bias....................................................................... 2100 3 . Statutory Attempts to Address Publication Bias....................................................................... 2101 4 . Publication Bias and Comparative Efficacy Claims .................................................................. 2106 5 . Government-Run Clinical Trials ........................ 2109 B. A “Significant Difference” Is Not Always a Significant Difference............................................. 2111 1. Statistical Significance Is a Measure of Certainty, Not Efficacy.................................... 2112 2 . When Is a “Significantly Effective” Drug Not Significantly Effective?. ...................... 2114 3 . Statistical Significance Is a De Minimis Requirement that Can Be Met by Diet, Exercise, and Other Mundane, Inexpensive Treatments.................... 2120 V. “Clinical Significance” Does Not Imply Greater Efficacy ............................................................................. 2122 A. The Law Requires Clinical Significance................... 2122 B. Clinical Significance Means Statistical Significance in Humans ............................................ 2123 C. Cases Addressing Absolute Efficacy Fail to Distinguish Clinical and Statistical Significance ................................................................ 2125 D. Cases Addressing Comparative Efficacy Fail to Distinguish Clinical and Statistical Significance................................................................ 2131 VI. Conclusion ........................................................................ 2133 17 . Id. 18 . Mirja L. Hamalainen et al., Ibuprofen or Acetaminophen for the Acute Controlled Crossover Study , 48 ( 1 ) NEUROLOGY 103, 106 ( 1997 ) (finding other measurements of pain relief were nevertheless statistically significant ). 19 . Seymour Diamond , Ibuprofen Versus Aspirin and Placebo in the Treatment of Muscle Contraction Headache , 23 ( 5 ) HEADACHE: J. HEAD & FACE PAIN 206 , 207 ( 1983 ). 20. Id. at 208 tbl.1 . 21. Id . 22 . See , e.g., J.M.A. Van Gerven et al., Self-Medication of a Single an Electronic Patient Diary , 42 BRIT. J. CLINICAL PHARMACOLOGY 475, 478 fig.1 ( 1996 ) (showing no advantage of ibuprofen over placebo during the first two Branding in Treatment of Headaches , 282 ( 6276 ) BRIT . MED. J. 1576 , 1577 tbl.II ( 1981 ) (reporting substantial improvements in headache pain for 86% of those given unbranded aspirin versus 74% of those given unbranded placebo); Roger REVIEW PROJECT , REVIEW NO. 4 , Sept . 2006 , at 10, http://effectivehealth 26. Drug Label for Cymbalta (duloxetine hydrochloride) Delayed-Release Capsules for Oral Use , Oct. 2010 , Reference ID 2860327, at 1, http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022516lbl.pdf. 27. Tracy Shier , Cymbalta Commercial (real one) , YOUTUBE (Nov. 2 , 2009 ), http://www.youtube.com/ watch?v= OTZvnAF7UsA (last visited Sept . 23 , 2013 ) (on file with the Washington and Lee Law Review) . 28 . Enbrel TV Spot Featuring Phil Mickelson , http://www.ispot.tv/ad/7VfC/ enbrel-featuring-phil-mickelson (last visited Apr . 10 , 2013 ) ( on file with the Washington and Lee Law Review). 30 . LowPricePlavix, Plavix TV Commercial, YOUTUBE (Aug. 30 , 2010 ), https://www.youtube.com/watch?v=oHRX0b4kPNY (last visited Oct . 21 , 2013 ) (on file with the Washington and Lee Law Review) . 42 . Jackson v. Astrue , No. 10 - 2226 , 2012 WL 580239, at * 1 ( 4th Cir. Feb . 23, 2012 ) (citing Mastro v . Apfel , 270 F.3d 171 , 176 ( 4th . Cir . 2001 )). 58 . Food and Drug Administration Modernization Act of 1997, Pub . L. No. 105- 115 , § 115 ( a ), 111 Stat. 2296 (codified at 21 U.S.C. § 355 (d)). 59 . See Adequate and Well-Controlled Studies , 21 C.F.R. § 126 ( b)(2) ( 2013 ) (emphasis added)) . 60 . See Matthew Wynia & David Boren , Better Regulation of Industry- Sponsored Clinical Trials Is Long Overdue , 37 J.L. MED . & ETHICS 410 , 411 ( 2009 ) (“For instance, it might take a billion dollars and ten years or more to bring a drug through testing to market . . . .”). 61 . Safety, of course, must also be a concern . See 21 C.F.R. § 314 .124( d ) ( 2013 ) (“The petitioner shall include in the petition information to show that the drug product was approved for safety and effectiveness . . . .”). 62 . FDA Reform Legislation: Hearings Before the Subcomm . on Health and Env't of the H . Comm. on Commerce, 104th Cong . 40 ( 1996 ) (statement of David A. Kessler , M.D. , Comm'r of Food & Drugs) . 63 . See supra Part II.B (discussing the evidence-efficacy dichotomy ). 64 . Bailey v. Wyeth, Inc., 37 A.3d 549 , 555 (N.J. Super . Ct. Law. Div. 2008 ). 65 . See supra notes 47-60 and accompanying text (discussing DESI in more depth) . 66 . Some commentators have also conflated the efficacy standard with the FDA Modernization Act of 1997 , 54 FOOD & DRUG L.J. 127 , 137 - 38 ( 1999 ) their CDER counterparts . . . on the basis of a single clinical trial . ”) . 67 . See AULAY MACKENZIE , MATHEMATICS AND STATISTICS FOR LIFE SCIENTISTS 4 ( 2005 ) (“Unfortunately, the terms 'accuracy' and 'precision' are important.”). 68 . See , e.g., B. ANTONISAMY ET AL., BIOSTATISTICS: PRINCIPLES AND PRACTICE 228 ( 2010 ) (“Often, a dartboard analogy . . . is . . . used to understand the JERROLD F. ROSENBAUM , NATURAL MEDICINES FOR PSYCHIATRIC DISORDERS 12 ( 2008 ) (“Double-blind, placebo-controlled, randomized clinical trials (RCTs) have Courtroom , 31 FLA. ST. U. L. REV . 303 , 320 ( 2004 ) (“The gold standard for randomized, controlled, double-masked study . ” (emphasis in original)) . 77 . 21 C.F.R. § 314 . 126 (b)(2) ( 2013 ). 78 . Laura Lee Johnson et al., An Introduction to Biostatistics: AND PRACTICE OF CLINICAL RESEARCH 165 , 167 (John I. Gallin & Frederick P. Ognibene eds., 2d ed. 2007 ). 79 . See infra notes 83-96 and accompanying text (discussing placebo control and blind testing) . 80 . Johnson et al., supra note 78, at 167. 81. Id. at 165-67 . 82 . See 21 C.F.R. § 314 . 126 (b)(2) ( 2013 ) (neglecting to set a minimum quantitative efficacy level) . 83. Id. § 314.126(b)(5) . 240. Gary W. Arendash & Chuanhai Cao , Caffeine and Coffee as Therapeutic Agents Against Alzheimer's Disease , 20 J. ALZHEIMER'S DISEASE S117 ( 2010 ). 241 . See Qi Dai et al., supra note 237 , at 751 ( finding fruits and vegetables to delay Alzheimer's); Colcombe & Kramer, supra note 238, at 128 (finding exercise to improve cognitive function of elderly adults). 242 . See Kroger et al., supra note 239 , at 2 (finding caffeine to be an effective treatment against Alzheimer's) . 243 . Raymond W. Lam et al., The Can-SAD Study: A Randomized with Winter Seasonal Affective Disorder, 163 AM. J. PSYCHIATRY 805 , 811 ( 2006 ). ANTIDEPRESSANTS: FINAL UPDATE 5 REPORT 47 ( 2011 ), http://www. healthandwelfare.idaho.gov/Portals/0/Medical/MedicaidCHIP/AntidepressantsFin


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Jonathan J. Darrow. Pharmaceutical Efficacy: The Illusory Legal Standard, Washington and Lee Law Review, 2018,