1 Bajcetic, Milos et al., Off-Label and Unlicensed Drugs Use in Paediatric Cardiology, 61 Eur. J. Clinical Pharmacology 775, 775 (2005)CrossRefGoogle ScholarPubMed (“[M]any of the drugs used in children in a variety of settings have been either not licensed for use in children (unlicensed) or have been prescribed outside the terms of their product license (off label prescriptions).”).

2 See, e.g., Pasquali, Sara K. et al., Oral Antihypertensive Trial Design and Analysis Under the Pediatric Exclusivity Provision, 144 Am. Heart J. 608, 609 (2002)CrossRefGoogle ScholarPubMed (“Although adults and children with hypertension are often treated with the same pharmacologic agents, there are some important differences between these 2 populations.”)

3 See Press Release, Food & Drug Administration, FDA Launches a Multi-Pronged Strategy to Strengthen Safeguards for Children Treated With Antidepressant Medications (Oct. 15, 2004), http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2004/ucm108363.htm (“The agency is directing manufacturers to add a ‘black box' warning to the health professional labeling of all antidepressant medications to describe this risk [of suicidality] and emphasize the need for close monitoring of patients started on these medications.”).

4 See Lawsuit Reveals Serious Safety Problems with the Nonsteroidal Anti-Inflammatory Drug Valdecoxib (BEXTRA), Worst Pills Best Pills Newsletter (Public Citizen), Sept. 2004, available at http://www.worstpills.org/public/newsletter.cfm?n_id=299. (“Valdecoxib is no better, and in some respects more dangerous, than drugs already on the market, including ibuprofen and naproxen which are available over-the-counter in non-prescription strengths.”)

5 Kesselheim, Aaron S. & Mello, Michelle M., Confidentiality Laws and Secrecy in Medical Research: Improving Access to Drug Safety Data, 26 Health Aff. 483, 488 (2007)CrossRefGoogle Scholar (describing FDA approval for valdecoxib (Bextra) and legal action seeking to reveal information about unapproved uses that was claimed as a trade secret).

6 First Amended Complaint at 27-28, United States ex rel. Kopchinski v. Pfizer, Inc., Civ. No. 05-cv-12115 (S.D. Fla., Oct. 24, 2005), available at http://www.drugepi.org/downloads/downloads/Pfizer_Complaint7.pdf. See id. at Document 32-9, page 2 (showing documents from Pfizer marketing efforts to position Bextra to “Meet All Arthritic & Pain Relief Needs”).

7 Levi, Marcel et al., Safety of Recombinant Activated Factor VII in Randomized Clinical Trials, 363 New Eng. J. Med. 1791, 1796-97 (2010)CrossRefGoogle ScholarPubMed (“This comprehensive study of the safety profile of [recombinant Factors VIIa] for off-label treatment of episodes of bleeding . . . found an increased risk of arterial thromboembolic events among patients who received off-label [recombinant Factors VIIa] as compared with patients who received placebo for bleeding episodes.”).

8 Caleb Alexander, G. et al., Increasing Off-Label Use of Antipsychotic Medications in the United States, 1995–2008, 20 Pharmacoepidemiology & Drug Safety 177, 182 (2010)Google Scholar (finding “a 45% decrease in the proportion of use for schizophrenia, for which most drugs were initially labeled, and a nearly seven-fold increase in use for bipolar affective disorder, representing a third of all uses with atypical agents in 2008”).

9 See Wang, Philip S. et al., Risk of Death in Elderly Users of Conventional vs. Atypical Antipsychotic Medications, 353 New Eng. J. Med. 2335, 2339 (2005)CrossRefGoogle ScholarPubMed (“In this study of 22,890 elderly persons beginning therapy with antipsychotic medications, patients for whom conventional agents were prescribed had a 37 percent higher, dose-dependent risk of death in the short term than those for whom atypical agents were prescribed”). See also Ray, Wayne A. et al., Atypical Antipsychotic Drugs and the Risk of Sudden Cardiac Death, 360 New Eng. J. Med. 225, 231 (2009)CrossRefGoogle ScholarPubMed (reporting that “a link between the use of typical antipsychotic drugs and both torsades de pointes and sudden cardiac death has been established”). As with the valdecoxib example, patients therefore receive unclear benefits and are exposed to important risks. See Schneider, Lon S. et al., Effectiveness of Atypical Antipsychotic Drugs in Patients with Alzheimer’s Disease, 355 New Eng. J. Med. 1525, 1537 (2006)CrossRefGoogle ScholarPubMed (concluding “there is no large clinical benefit of treatment with atypical antipsychotic medications as compared with placebo”).

10 Press Release, Food & Drug Administration, Public Health Advisory: Deaths with Antipsychotics in Elderly Patients with Behavioral Disturbances (Apr. 11, 2005), available at http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/PublicHealthAdvisories/ucm053171.htm (“The Food and Drug Administration has determined that the treatment of behavioral disorders in elderly patients with dementia with atypical (second generation) antipsychotic medications is associated with increased mortality.”).

11 Lucette Lagnado, Prescription Abuse Seen in U.S. Nursing Homes, Wall St. J., Dec. 4, 2007, at A1 (reporting that in 2005 “Medicaid spent $5.4 billion on atypical antipsychotic drugs” but only $1.58 billion on AIDS drugs and $2.1 billion on medications to lower cholesterol).

12 See Robert Pear, Health Spending Rose in ’09, but at Low Rate, N.Y. Times, Jan. 5, 2011, at A19 (reporting that “[p]artly offsetting the slowdown in private health spending was a rapid increase in Medicaid spending, driven by the addition of 3.5 million people to the rolls”).

13 Dissemination of journal reprints is now allowed if the information is based on well-controlled clinical studies; the information is truthful and not misleading; the information is accompanied by disclaimer, approved labeling, disclosure of known risks, and a bibliography of related publications; the journal is independent and adheres to standard peer-review and editorial processes; the information is not accompanied by promotional materials; and the information is not distributed to consumers. This policy changes a previous rule that restricted dissemination to off-label uses associated with the filing of a supplemental New Drug Application. See infra notes 59-60. The prior policy also required submission of the disseminated materials to FDA in advance. See infra notes 137-39 and accompanying text.

14 See Wazana, Ashley, Physicians and the Pharmaceutical Industry: Is a Gift Ever Just a Gift?, 283 JAMA 373, 377 (2000)CrossRefGoogle ScholarPubMed (“Residents and physicians interact with the pharmaceutical industry frequently and in multiple settings and fashions, beginning as early as medical school.”). See generally Manchanda, Puneet & Honka, Elizabeth, The Effects and Role of Direct-to-Physician Marketing in the Pharmaceutical Industry: An Integrative Review, 5 Yale J. Health Pol’y L. & Ethics 785, 787 (2005)Google Scholar (concluding that “detailing [is] an important source of information, [and] it affects physician prescription behavior in a positive and significant manner”).

15 Kesselheim, Aaron S. et al., Strategies and Practices in Off-Label Marketing of Pharmaceuticals: A Retrospective Analysis of Whistleblower Complaints, 8 PLoS Med. 1, 3 (2011)CrossRefGoogle ScholarPubMed (identifying $7.9 billion in civil and criminal fines related to off-label marketing investigations from 2004-2010).

16 See Coté, Timothy et al., Orphan Products: An Emerging Trend in Drug Approvals, 9 Nature Reviews Drug Discovery 84, 84 (2010)CrossRefGoogle ScholarPubMed (describing growth in approval of orphan drugs).

17 Walton, Surrey M. et al., Prioritizing Future Research on Off-Label Prescribing: Results of a Quantitative Evaluation, 28 Pharmacotherapy 1443, 1443 (2008)CrossRefGoogle ScholarPubMed (“Future research into off-label drug use should focus on drugs used frequently with inadequate supporting evidence, particularly if further concerns are raised by known safety issues, high drug cost, recent market entry, and extensive marketing”).

18 Chokshi, Dave A. et al., Designing Comparative Effectiveness Research on Prescription Drugs: Lessons from the Clinical Trial Literature, 29 Health Aff. 1842, 1843 (2010)CrossRefGoogle ScholarPubMed (providing an overview of the recent legislation encouraging comparative effectiveness research, as well as past examples of these kinds of studies).

19 Admittedly, manufacturers are free to file with the FDA for a label extension. Administrative fees and the burden of time may reduce their incentive to do so; these hurdles underlie some of the proposed policy solutions in the final section of this article. Another reason why they might not file could be that the data are hard to collect. We should be more skeptical of this stated rationale, in part because it could disguise the fact that the data do not support the use. See Miller, Franklin G. & Joffe, Steven, Equipoise and the Dilemma of Randomized Clinical Trials, 364 New Eng. J. Med. 476, 480 (2011)CrossRefGoogle ScholarPubMed (concluding that “[a]s a rule, to inform regulatory and coverage decisions, rigorous evaluation of a new treatment before it is made available in clinical practice must be pursued beyond the point at which physicians and informed patients would choose it over the current standard treatment based on initial efficacy data”). See also Avorn, Jerry & Kesselheim, Aaron S., A Hemorrhage of Off-Label Use, 154 Annals Internal Med. 566, 567 (2011)CrossRefGoogle ScholarPubMed (commenting on articles presenting data regarding recombinant Factor VIIa (NovoSeven), a drug intended for the rare indication of hemophilia but for which there was “rapidly increasing use . . . that does not benefit patients and increases the risk of dangerous thrombotic events”).

20 Notably, non-evidence-based uses of drugs for a condition for which they were FDA-approved have been reported. This rare situation occurs when the approved indication is too broad. In the rofecoxib case, for example, the drug was used widely to manage pain—consistent with its general indication—despite the fact that the evidence showed no efficacy over other non-steroidal anti-inflammatory drugs. In fact, the totality of the evidence only supported its use in a limited number of patients who might need such therapy but are also at high risk for gastrointestinal bleeds and low risk of cardiovascular events. See infra notes 110-13 and accompanying text for the example of rofecoxib (Vioxx). In that case, the label did not correctly describe the risks and benefits of the drug in order to optimally inform physician prescribing practices. Another example occurs when drugs are approved in a certain condition, showing efficacy but not superior comparative effectiveness to currently available therapies, and are then used widely despite the potential for enhanced risk of adverse events. See, e.g., Graham, David J. et al., Risk of Acute Infarction Myocardial, Stroke, Heart Failure, and Death in Elderly Medicare Patients Treated with Rosiglitazone or Pioglitazone, 304 JAMA 411, 411 (2010)CrossRefGoogle ScholarPubMed (concluding “rosiglitazone was associated with an increased risk of stroke, heart failure, and all-cause mortality and an increased risk of the composite of AMI, stroke, heart failure, or all-cause mortality in patients 65 years or older”). This phenomenon occurs routinely in medical practice, including the recent case of rosiglitazone (Avandia), an anti-diabetic agent linked to enhanced cardiovascular disease. These concepts are outside the scope of the current discussion.

21 See Greene, Jeremy A. & Kesselheim, Aaron S., Pharmaceutical Marketing and the New Social Media, 363 New Eng. J. Med. 2087, 2087 (2010)CrossRefGoogle ScholarPubMed (describing the legislative origin of the drug label).

22 See Kefauver-Harris Drug Amendments of 1962, Pub. L. No. 87-781, § 131, 76 Stat. 780, 791 (codified as amended at 21 U.S.C. § 352(n) (2006)).

23 21 C.F.R. § 312.23(a)(3)(iv) (2004).

24 Phase 1 studies are often performed using healthy adult volunteers. For specific drugs that are predicted, based on pre-clinical studies, to have activity against certain diseases, such as cancer, Phase 1 studies may be performed in patients with the condition the drug is intended to treat. However, such studies are frequently referred to as “Phase 1/2” hybrid studies.

25 21 C.F.R. § 312.21(b) (2004).

26 Id. § 312.21(c).

27 See Winkelmayer, Wolfgang C., Against TREATing all Patients Alike: Lessons from an FDA Advisory Committee Meeting, 22 J. Am. Soc’y Nephrology 1, 1-2 (2011)CrossRefGoogle ScholarPubMed (describing the details of an Advisory Committee discussion regarding safety of darbepoetin (Aranesp)).

28 See Roboz, Gail J. et al., Efficacy and Safety of Gemtuzumab Ozogamicin in Patients with Poor-Prognosis Acute Myeloid Leukemia, 43 Leukemia & Lymphoma 1951, 1951 (2002)CrossRefGoogle ScholarPubMed (describing the efficacy of the drug as well as neutropenic fever, the major side effect).

29 Notably, this drug was removed from the market in 2010 when new evidence emerged that suggested the risk of adverse events was higher than expected and the efficacy was lower than previously thought. See Lisa Richwine, Pfizer Pulls Leukemia Drug from U.S. Market, Reuters (June 21, 2010, 6:28 PM), http://www.reuters.com/article/idUSTRE65K5QG20100621 (describing action by FDA in ogozamicin (Mylotarg) case).

30 An FDA Advisory Committee voted 1-14 against approving it for AML, although at the same time, the Committee voted 9-6 in favor of approving clofarabine for acute lymphoblastic leukemia, a different blood malignancy. See Food & Drug Admin., Ctr. for Drug Evaluation and Research, Approval Package For: Application Number 21-673 14-15 (Dec. 28, 2004), available at http://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-673_Clolar_medr.PDF (describing results of Advisory Committee votes).

31 21 C.F.R. § 201.56 (2010).

32 Kesselheim, Aaron S. et al., The Rise and Fall of Natrecor for Congestive Heart Failure: Implications for Drug Policy, 25 Health Aff. 1095, 1096-97 (2006)CrossRefGoogle ScholarPubMed (describing premarketing clinical trials).

33 Sackner-Bernstein, Jonathan D. et al., Risk of Worsening Renal Function with Nesiritide in Patients with Acutely Decompensated Heart Failure, 111 Circulation 1487, 1487 (2005)CrossRefGoogle ScholarPubMed (describing meta-analysis results showing increased risk linked to nesiritide use).

34 Mills, Roger M. et al., Sustained Hemodynamic Effects of an Infusion of Nesiritide (Human B-type Natriuretic Peptide) in Heart Failure: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial, 34 J. Am. College Cardiology 155, 160 (1999)CrossRefGoogle ScholarPubMed (reporting in this early-stage study that “[t]hree deaths occurred during the 15-day study follow-up period, one each in the placebo group, the 0.03-mg/kg/min nesiritide group and the 0.06-mg/kg/min nesiritide group” but “[n]one of these deaths was believed to be study related”).

35 Jerry Avorn, Powerful Medicines: The Benefits, Risks, and Costs of Prescription Drugs 55-61 (2005).

36 Epogen was actually approved as an “orphan drug,” a formal regulatory category of drugs that are intended for use in diseases with a prevalence of less than 200,000 people in the U.S. Kesselheim, Aaron S., Using Market Exclusivity Incentives to Promote Pharmaceutical Innovation, 363 New Eng. J. Med. 1855, 1857 (2010)CrossRefGoogle ScholarPubMed (describing the Orphan Drug Act and related policy controversy surrounding it).

37 Singh, Ajay K. et al., Correction of Anemia with Epoetin Alfa in Chronic Kidney Disease, 355 New Eng. J. Med. 2085, 2092 (2006)CrossRefGoogle ScholarPubMed (describing results of a randomized trial of correcting anemia in patients with chronic kidney disease to a high level of hemoglobin showing that such a strategy was associated with increased adverse events and no observed benefits).

38 Pitt, Bertram et al., The Effect of Spironolactone on Morbidity and Mortality in Patients with Severe Heart Failure, 341 New Eng. J. Med. 709, 712 (1999)CrossRefGoogle ScholarPubMed (finding that “treatment with spironolactone reduced the risk of death from all causes, death from cardiac causes, hospitalization for cardiac causes, and the combined end point of death from cardiac causes or hospitalization for cardiac causes among patients who had severe heart failure”).

39 Juurlink, David N. et al., Rates of Hyperkalemia After Publication of the Randomized Aldactone Evaluation Study, 351 New Eng. J. Med. 543, 549 (2004)CrossRefGoogle ScholarPubMed (reporting “the publication of RALES was associated with an abrupt increase in the rate of prescriptions for spironolactone among older patients”).

40 Dave A. Chokshi et al., supra note 18, at 1844-45 (describing the policy lessons from the RALES study).

41 See Strom, Brian L. et al., Post-Marketing Studies of Drug Efficacy: Why?, 78 Am. J. Med. 475, 478 (1985)CrossRefGoogle ScholarPubMed (calculating off-label uses to demonstrate the need for post-marketing studies of drug efficacy).

42 Alison Young & Chris Adams, Prescribing Drugs ‘Off-Label’ Routine but Can Harm Patients, McClatchy Newspapers (Nov. 2, 2003), http://www.mcclatchydc.com/2003/11/02/28122/prescribing-drugs-off-label-routine.html# (finding that off-label prescribing “is often driven by questionable research, aggressive drug-company marketing and cavalier doctors, and condoned by tepid regulators”).

43 Radley, David C. et al., Off-Label Prescribing Among Office-Based Physicians, 166 Archives Internal Med. 1021, 1023 (2006).CrossRefGoogle ScholarPubMed

44 See Mortenson, Lee E., The Off-Label Debate: A Threat to the Future of Cancer Care, 9 Cancer Investigation 597, 599 (1991)CrossRefGoogle ScholarPubMed (supporting off-label use in oncology). See also U.S. Gen. Accounting Office, Off-Label Drugs: Reimbursement Policies Constrain Physicians in Their Choice of Cancer Therapies (1991), available at http://161.203.16.4/d18t9/144933.pdf (finding widespread use of cancer drugs).

45 Am. Soc'y of Clinical Oncology, Reimbursement for Cancer Treatment: Coverage of Off-Label Drug Indications, 24 J. Clinical Oncology 3206, 3206 (2006)CrossRefGoogle Scholar (supporting insurance coverage for use of drugs for oncologic conditions despite those uses not having been approved by the FDA).

46 de Gramont, Aimery & van Cutsem, Eric, Investigating the Potential of Bevacizumab in Other Indications: Metastatic Renal Cell, Non-Small Cell Lung, Pancreatic and Breast Cancer, 69 Oncology 46, 54 (2005)Google ScholarPubMed (reviewing available evidence supporting off-label use of bevacizumab (Avastin) for numerous cancers outside of the approved indications by the FDA). See also Nat'l Cancer Institute, Q & A: Off-Label Drugs, http://newscenter.cancer.gov/clinicaltrials/learning/approval-process-for-cancer-drugs/allpages/print (last updated Jan. 6, 2004) (noting “once a drug is on the market further research may show that it also acts on different biological targets present in other kinds of cancer”). A survey of oncologists in 1998 indicated that over 60% had used a drug off-label. Nat'l Cancer Institute, Understanding the Approval Process for New Cancer Treatments: Why Is Off-Label Use of Drugs so Common in Cancer Treatment, http://www.cancer.gov/clinicaltrials/education/approval-process-for-cancer-drugs/allpages#Anchor-Wh-36735 (last visited Apr. 18, 2011) (relying on an American Cancer Society study reporting results from a survey of 200 oncologists).

47 See Sox, Harold C., Evaluating Off-Label Uses of Anticancer Drugs: Time for a Change, 150 Annals Internal Med. 353, 354 (2009)CrossRefGoogle ScholarPubMed (concluding “even an enhanced compendia-based system is too weak to deal with the methodological challenges of the evidence base for off-label indications”).

48 See Griggs, Jennifer J. et al., Social and Racial Differences in Selection of Breast Cancer Adjuvant Chemotherapy Regimens, 25 J. Clinical Oncology 2522, 2525 (2007)CrossRefGoogle ScholarPubMed (finding “[t]he use of nonstandard regimens was associated independently with patient educational level, black race, and cancer stage”).

49 Abernethy, Amy P. et al., Reliability of Compendia Methods for Off-Label Oncology Indications, 150 Annals Internal Med. 336, 341 (2009)CrossRefGoogle ScholarPubMed (finding “little agreement between the results of systematic reviews of 14 off-label indications of cancer drugs and the evidence cited for those indications in these commonly used compendia”).

50 Kocs, Darren & Mark Fendrick, A., Effect of Off-Label Use of Oncology Drugs on Pharmaceutical Costs: The Rituximab Experience, 9 Am. J. Managed Care 393, 393 (2003)Google ScholarPubMed (describing substantial use of rituximab at one institution).

51 Meropol, Neal J. & Schulman, Kevin, Cost of Cancer Care: Issues and Implications, 25 J. Clinical Oncology 180, 181 (2007)Google ScholarPubMed (considering $5.3 billion to include “$2.3 billion for chemotherapy and $1.5 billion for erythroid growth factors”).

52 Halbert, R.J. et al., Outpatient Cancer Drug Costs: Changes, Drivers, and the Future, 94 Cancer 1142, 1145 (2002)CrossRefGoogle ScholarPubMed (concluding “[a]ntineoplastic therapy constituted the largest component of cancer-related drug costs (67%)”).

53 Ramsey, Scott D., How Should We Pay the Piper When He’s Calling the Tune? On the Long-Term Affordability of Cancer Care in the United States, 25 J. Clinical Oncology 175, 175-76 (2007)CrossRefGoogle ScholarPubMed (“In a market with distortions created by monopolies, inelastic demand, health insurance, and prescribing incentives, it is not surprising that we are seeing outrageous prices for new cancer therapies.”).

54 Nadler, Eric et al., Do Oncologists Believe New Cancer Drugs Offer Good Value?, 11 Oncologist 90, 94 (2006)CrossRefGoogle ScholarPubMed (finding in a survey “oncologists implied that very small gains in life expectancy were not worth the costs”).

55 There are important limitations on insurers' ability to limit coverage—for example, intravenous chemotherapeutic drugs for oncology, which are reimbursed by Medicare Part B, cannot by law restrict coverage of an off-label use if the use is covered in one of the listed compendia. See Bach, Peter B., Limits on Medicare’s Ability to Control Rising Spending on Cancer Drugs, 360 New Eng. J. Med. 626, 626 (2009)CrossRefGoogle ScholarPubMed (describing the drug compendia used in cancer care reimbursement). Numerous concerns have been raised in recent years about the process by which off-label uses are listed in compendia and whether they reflect accurate evidence or are too aggressive. Similarly, Medicare Part D features six protected classes where everything gets in the formulary. See Outterson, Kevin & Kesselheim, Aaron S., How Medicare Could Get Better Prices on Prescription Drugs, 28 Health Aff. w832, w835-w836 (2009)CrossRefGoogle ScholarPubMed (describing the formulary design of Medicare Part D programs).

56 Steinman, Michael A. et al., Narrative Review: The Promotion of Gabapentin: An Analysis of Internal Industry Documents, 145 Annals Internal Med. 284, 284 (2006)CrossRefGoogle ScholarPubMed (describing the process by which the manufacturer of gabapentin systematically promoted the drug for unapproved uses).

57 Surrey M. Walton et al., supra, note 17, at 1448 (finding antipsychotics to be in a small group of drugs with “a high volume of off-label prescribing in the absence of good evidence”).

58 Chen, Hua et al., An Epidemiological Investigation of Off-Label Anticonvulsant Drug Use in the Georgia Medicaid Population, 14 Pharmacoepidemiology & Drug Safety 629, 636 (2005)CrossRefGoogle ScholarPubMed (finding “the study results reveal that many off-label prescribing decisions do not find support in randomized clinical trials or other well-designed studies”).

59 A so-called supplemental New Drug Application (sNDA). See Helm, Katherine A., Protecting Public Health from Outside the Physician’s Office: A Century of FDA Regulation from Drug Safety Labeling to Off-Label Drug Promotion, 18 Fordham Intell. Prop. Media & Ent. L.J. 117, 134 (2007)Google Scholar (“Because proof of effectiveness was not generalizable to a given drug product, the FDA introduced a process whereby the drug sponsor had to file a Supplemental New Drug Application (sNDA) for separate FDA approval of each new therapeutic use of an approved drug.”).

60 In the case of the gastrointestinal motility agent cisapride (Propulsid), the FDA negotiated for five years with the manufacturer to change the drug's label to include adverse event data that had been submitted to the FDA but not made publicly available. Gardiner Harris & Eric Koli, Lucrative Drug, Danger Signals and the FDA, N.Y. Times, June 10, 2005, at A1, C6 (noting “much of the conversation between the company and regulators remained private as the drug thrived”). This problem was addressed in the FDA Amendments Act of 2007, but the effectiveness of these changes is not yet clear. See Food and Drug Administration Amendments Act of 2007, Pub. L. No. 110-85, 121 Stat. 823 (2007).

61 Of course, an alternative explanation for why an evidence-based off-label use has not been submitted for approval to the FDA is that the “evidence” is weak or non-existent, and the manufacturer is content to allow profitable off-label prescribing without further scrutiny. The final section, which discusses a proposal to scale regulation of off-label uses based on degree of departure from the approved use, addresses this question by trying to engage the FDA in more reviews of off-label uses, even if some are more expedited. See infra Part IV. The Cochrane Database Library and comparative effectiveness research institutions in non-U.S. settings (such as the United Kingdom's National Institute for Health and Clinical Excellence) sometimes engage reviews of widespread off-label uses. In the U.S., the Agency for Healthcare Research & Quality now undertakes many of these sorts of literature reviews. See Agency for Healthcare Quality & Research, Comparative Effectiveness of Off-Label Use of Atypical Antipsychotics, Comparative Effectiveness Review No. 6 (2007), available at http://www.effectivehealthcare.ahrq.gov/ehc/products/5/63/Atypical_Antipsychotics_Final_Report.pdf (reviewing “the scientific evidence on the safety and effectiveness of such off-label uses”).

62 Choonara, Imti & Conroy, Sharon, Unlicensed and Off-Label Drug Use in Children: Implications for Safety, 25 Drug Safety 1, 1 (2002)CrossRefGoogle ScholarPubMed (“A significant number of children receive either an unlicensed or an off-label drug during their stay in hospital.”).

63 Rayburn, W.F. & Turnbull, G.L., Off-Label Drug Prescribing on a State University Obstetric Service, 40 J. Reprod. Med. 186, 186 (1995)Google ScholarPubMed (supporting off-label use under circumstances where “[t]he primary purposes were to avoid an obstetric complication (premature labor and delivery, preeclampsia/eclampsia) or improve the capacity for eventual postnatal adaptation”).

64 Donofrio, Peter D. & Busis, Neil A., Regulatory and Reimbursement Issues in Treating Patients with Immune-Mediated Neuropathies, 59 Neurology 498, 498 (2002)CrossRefGoogle ScholarPubMed (describing use of a drug to treat diseases with substantial morbidity, including “many neurologic conditions that have a proven or presumed autoimmune or inflammatory pathogenesis”). See also Tabarrok, Alexander T., Assessing the FDA via the Anomaly of Off-Label Drug Prescribing, 5 Indep. Rev. 25, 28 (2000)Google Scholar (“Off-label prescribing is also common when doctors must prescribe drugs for so-called orphan populations and orphan diseases—populations too small and diseases too rare to justify the expense of petitioning the FDA for new labeling.”).

65 Notably, off-label use may also be subject to non-governmental regulation. Some payers have attempted to regulate off-label use of drugs by restricting the use of particular expensive drugs to on-label indications. For example, Medicare has traditionally limited reimbursement of certain oncology drugs to indications listed by a few reference guides or compendia, which include both on- and off-label indications supported by the medical literature. See Tillman, Katherine et al., Compendia and Anticancer Therapy Under Medicare, 150 Annals Internal Med. 348, 349 (2009)CrossRefGoogle ScholarPubMed (describing the compendia publication process). In 2009, however, Medicare loosened its policies to allow more reimbursement of treatments with scant supporting data. Reed Abelson & Andrew Pollack, Medicare Widens Drugs it Accepts for Cancer, N.Y. Times, Jan. 27, 2009, at A1, A22 (reporting that “[t]he new rules expand the number of reference guides—or compendiums—that Medicare relies on for determining which off-label uses of cancer drugs to cover”). In addition, a number of state laws limit the ability of private payers to curb the utilization of cancer drugs by mandating coverage of cancer drugs in many cases. See Bach, supra note 56, at 631 (classifying states based on the strictness of their laws mandating coverage of certain off-label uses). Such policies may increase the prevalence of non-evidence-based off-label uses, but may also reduce the incentive to develop comparative effectiveness studies. This article does not address other limits on off-label promotion and/or use other than those imposed by the government.

66 In the past, FDA guidance on marketing prescription drugs in new media has primarily addressed how to provide “fair balance,” a regulatory principle that mandates adequate space in promotional materials be given to risks as well as benefits of products. Greene, Jeremy A. & Herzberg, David, Hidden in Plain Sight: Marketing Prescription Drugs to Consumers in the Twentieth Century, 100 Am. J. Pub. Health 793, 799 (2010)CrossRefGoogle ScholarPubMed (describing the principle of fair balance).

67 Kesselheim, Aaron S. & Avorn, Jerry, Pharmaceutical Promotion to Physicians and First Amendment Rights, 358 New Eng. J. Med. 1727, 1727 (2008)CrossRefGoogle ScholarPubMed (describing off-label promotion rules).

68 See Mello, Michelle M. et al., Shifting Terrain in the Regulation of Off-Label Promotion of Pharmaceuticals, 360 New Eng. J. Med. 1557, 1557 (2009)CrossRefGoogle Scholar (describing the regulatory landscape of off-label promotion and noting “the FDA's concern for its reputation as an oversight agency has probably also influenced its regulatory strategy”).

69 This review is contemporary to the dissemination of the advertisement, as pharmaceutical manufacturers are “required to submit to FDA copies of promotional materials for prescription drug products at the time of initial dissemination.” Marketing or Medicine: Are Direct-to-Consumer Ads Playing Doctor?: Hearing Before the Special Comm. on Aging, 110th Cong. 63 (2008) (statement of Daniel Shultz, Dir., Ctr. for Devices & Radiological Health), available at http://www.fda.gov/NewsEvents/Testimony/ucm096272.htm. Therefore, an inappropriate advertisement may become public long before any off-label promotion is realized and distribution is restricted.

70 See, e.g., Food & Drug Admin., Division of Drug Marketing, Advertising and Communication, Warning Letter Pfizer, Inc. (2005) (warning the manufacturer of the antibiotic linezolid (Zyvox) about inappropriate off-label statements in its advertising materials).

71 Stryer, Daniel & Bero, Lisa A., Characteristics of Materials Distributed by Drug Companies: An Evaluation of Appropriateness, 11 J. Gen. Internal Med. 575, 575 (1996)CrossRefGoogle ScholarPubMed (presenting results from a study of advertising materials showing “[f]orty-two percent of the items failed to comply with at least one of three FDA regulations assessed”). See Ziegler, Michael G. et al., The Accuracy of Drug Information from Pharmaceutical Sales Representatives, 273 JAMA 1296, 1297 (1995)CrossRefGoogle ScholarPubMed (finding “[t]hirteen percent of the statements pharmaceutical representatives made about their drugs were inaccurate” and that “[a]ll those statements made their drug appear better than it actually was”). Recently, the FDA instituted a “Bad Ad” program to enlist providers' help in identifying promotional materials that might break its rules. See Food & Drug Admin., Truthful Prescription Drug Advertising and Promotion (Bad Ad Program), http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/DrugMarketingAdvertisingandCommunications/ucm209384.htm (last updated Mar. 31, 2011).

72 See Lurie, Peter et al., Violations of Exhibiting and FDA Rules at an American Psychiatric Association Annual Meeting, 26 J. Pub. Health Pol’y 389, 389 (2005)CrossRefGoogle ScholarPubMed (reporting “[o]ver half of all companies (54%) were in violation of either [American Psychiatric Association] rules or FDA regulations”).

73 Kesselheim et al., supra note 15 (presenting a full list of pharmaceutical manufacturers engaged in settlements related to off-label drug promotion from 2004 to October 2010).

74 Johnson, Sandra H., Polluting Medical Judgment? False Assumptions in the Pursuit of False Claims Regarding Off-Label Prescribing, 9 Minn. J. L. Sci. & Tech. 61, 114-15 (2008)Google Scholar (“In August, 2004, two years into the state and federal governments' pursuit of the lawsuit and shortly after the attention-grabbing settlement, sales of Neurontin had actually increased by 32% over the same quarter the year before. Lehman Brothers estimated that the great bulk of those prescriptions for Neurontin—90% of sales, in fact—were still for off-label uses.”).

75 Jeffrey Kindler, Business Must Change to Earn Back the Public’s Trust, Reuters (Mar. 17, 2010, 11:28 AM), http://blogs.reuters.com/great-debate/2010/03/17/business-must-change-to-earn-back-the-publics-trust/ (“This new era of responsibility starts with acknowledging where we've gone wrong, showing that we're making real changes, and demonstrating that we are willing to work together to address society's most urgent problems.”). See also Michael McCaughan, The Era of Big Pharma Fraud Cases is Ending, Former U.S. Attorney Loucks Says – But It May Go Out with a Bang, Pink Sheet (Mar. 22, 2010) (acknowledging that pharmaceutical manufacturers are “stopping some of the conduct that they may have been incenting with some of their compensation programs”).

76 The InterMune case included a deferred prosecution agreement for criminal charges, but no fine.

77 See Klein, Daniel B. & Tabbarok, Alexander, Who Certifies Off-Label?: FDA Efficacy Requirements May Do More Harm Than Good, 27 Regulation 60, 63 (2004)Google Scholar (“The experience with off-label prescribing and the experience of pre-1962 America suggest that initial efficacy requirements may do more harm than good.”).

78 See Hall, Ralph F. & Sobotka, Elizabeth S., Inconsistent Government Policies: Why FDA Off-Label Regulation Cannot Survive First Amendment Review Under Greater New Orleans, 62 Food & Drug L.J. 1, (2007).Google ScholarPubMed

79 Mathew, Ninan T. et al., Efficacy of Gabapentin in Migraine Prophylaxis, 41 Headache 119, 119 (2001)CrossRefGoogle ScholarPubMed (reporting fewer migraines in gabapentin-treated group than a placebo group).

80 Kesselheim & Avorn, supra note 67, at 1729 (describing the commercial speech doctrine).

81 Va. State Bd. of Pharm. v. Citizens Consumer Council, 425 U.S. 748, 763-64 (1976). Since that time, the introductory inquiry regarding a piece of legislation or regulatory action has been whether it covers any type of speech. The First Amendment does not extend to conduct merely because speech is involved in carrying out the conduct. Id.

82 Id. at 765.

83 Cent. Hudson Gas & Elec. Corp. v. Pub. Serv. Comm'n, 447 U.S. 557, 566 (1980).

84 Thompson v. W. States Med. Ctr., 535 U.S. 357 (2002).

85 Id. at 369.

86 Id. at 376.

87 Id. at 371.

88 Letter from Karen L. Goldenthal, Director of the Division of Vaccines and Related Products Applications, Center for Biologics Evaluation and Research, to Peter Kresel, Senior Vice President of Global Regulatory Affairs, Allergan, Inc. (Apr. 12, 2002), available at http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/ucm088278.pdf (noting Botox's approval for cervical dystonia).

89 Botox Approved for Severe Underarm Sweating, WebMD Health News (July 20, 2004), http://www.webmd.com/skin-beauty/news/20040720/botox-approved-for-severe-underarm-sweating (describing FDA action approving Botox).

90 Notably, despite its widespread cosmetic use, onabotulinumtoxinA provides another example of the same post-marketing safety concerns that can be found in FDA-approved drug products. Early studies in small numbers of patients suggested that the product is quickly broken down after injection. However, some research has concluded that the injectable product can travel up neurons and collect in brain tissue, disrupting neuronal activity. See Antonucci, Flavia et al., Long-Distance Retrograde Effects of Botulinum Neurotoxin A, 28 J. Neuroscience 3689, 3689 (2008)CrossRefGoogle ScholarPubMed (finding “a novel pathway of [botulinum toxin] trafficking in neurons”). In 2009, the FDA required the manufacturer to add a black box warning to use of onabotulinumtoxinA highlighting the possibility of experiencing potentially life-threatening distant spread of toxin effect from the injection site after local injection. Press Release, Food & Drug Admin., OnabotulinumtoxinA (Marketed as Botox/Botox Cosmetic), AbobotulinumtoxinA (Marketed as Dysport) and RimabotulinumtoxinB (Marketed as Myobloc) Information (Aug. 3, 2009), http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm175011.htm.

91 Allergan, Inc. v. United States et al., No. 1:09-cv-01879 (D.C. Cir. Oct. 1, 2009).

92 Sue Reisinger, Let Me Speak, Corporate Counsel Online, Dec. 1, 2009, available at http://www.law.com/jsp/cc/PubArticleFriendlyCC.jsp?id=1202435295699 (“Allergan's challenge could pose a threat to the commercial speech doctrine, which limits the First Amendment rights of companies and allows the government to regulate what their representatives can say.”).

93 Nathan Olivarez-Giles, Botox Maker Allergan Seeks to Lift U.S. Ban on Marketing Unapproved Uses, L.A. Times, Oct. 3, 2009, at B3 (estimating “about 20 percent of Botox use in the U.S. is off label”).

94 Brenda Sandburg, Off-Label Promotion: FDA Court Filing Says it Must Retain Enforcement Flexibility, Citing Harms from Premarin and ESAs, Pink Sheet, Apr. 12, 2010, at 17 (describing numerous alternatives to current FDA restrictions on off-label promotion). The FDA responded that such a distinction was impossible, and that any narrow definition of “off-label promotion” that would try to distinguish non-promotional speech would be subject to exploitation by manufacturers. See id.

95 The drug was approved by the FDA for upper limb spasticity similar to the kind proposed in the complaint in 2010. The FDA also approved the drug for use in migraines, which was a central component in the DOJ enforcement action, just a few weeks after the settlement was announced.

96 Complaint at 2, United States ex rel. Lang and Rushin v. Allergan, Inc., No. 1:07-cv-1288 (N.D. Ga. June 5, 2007).

97 Press Release, Dep't of Justice, Allergan Agrees to Plead Guilty and Pay $600 Million to Resolve Allegations of Off-Label Promotion of Botox (Sept. 1, 2010), http://www.justice.gov/opa/pr/2010/September/10-civ-988.html (describing details of settlement agreement).

98 Press Release, Food & Drug Admin., FDA Approves Botox to Treat Chronic Migraine (Oct. 15, 2010), http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm229782.htm (detailing newly approved secondary indication for Botox in management of migraine headaches).

99 See Brief for Petitioner at 26-34, Sorrell v. IMS Health Inc., 630 F.3d 262 (2d Cir. 2010) (No. 10-779) (indicating that twenty-five additional states and the District of Columbia have passed similar laws concerning the restriction of commercial use of prescriber-identifiable data and that implications of loss of privacy in data mining necessitates judicial clarification of relevant First Amendment principles).

100 Lorillard Tobacco Co. v. Reilly, 533 U.S. 525, 564 (2001) (finding that “[t]he State's interest in regulating underage tobacco use is substantial”).

101 Hoefges, Michael, Protecting Tobacco Advertising Under the Commercial Speech Doctrine: The Constitutional Impact of Lorillard Tobacco Co., 8 Comm. L. & Pol’y 267, 297 (2003).Google Scholar

102 Bipartisan Campaign Reform (McCain-Feingold) Act of 2002, Pub. L. No. 107-155, 166 Stat. 81, 91-92.

103 See Citizens United v. Fed. Election Comm'n, 130 S. Ct. 876 (2010).

104 See Michael Loucks, Acting U.S. Attorney for the Dist. of Mass., Justice Department Press Conference on the Health Care Fraud Settlement with Pfizer (Sept. 2, 2009), http://findarticles.com/p/news-articles/political-transcript wire/mi_8167/is_20090902/secretary-health-human-services kathleen/ai_n50917511/pg_6/?tag=content;col1 (“Any indication not on the label is off-label, and selling an approved drug intending that it be used for an off-label use is a violation of the law.”).

105 Citizens United, 130 S. Ct. at 885 (quoting McConnell v. Fed. Election Comm'n, 540 U.S. 93, 196 (2003)).

106 Id. (quoting Buckley v. Valeo, 424 U.S. 1, 76 (1976)).

107 Id. at 915.

108 The Supreme Court will get another opportunity to rule on the issue of pharmaceutical marketing and commercial speech in the upcoming case of Sorrell v. IMS Health, which involves a Vermont law that outlawed the practice of “data mining,” or pharmacies' selling of physician-identifiable prescription data for commercial use. Vt. Stat. Ann. tit. 18, § 4631(d) (2007). The data allow pharmaceutical promotion to be extremely physician-specific, because the detailers know exactly what, where, and when each physician has prescribed. The Vermont law allowed physicians to opt-in to receive such information, but otherwise prevented its sale for commercial purposes. Though approved at the District Court level, the law was overturned by the Second Circuit Court of Appeals on the basis that it was an impermissible restriction on commercial speech under Central Hudson in part because “Vermont does have more direct, less speech restrictive means available” to accomplish its goals. Sorrel, 630 F.3d at 280. In contrast, similar laws in New Hampshire and Maine have been validated by the First Circuit Court of Appeals. IMS Health, Inc. v. Ayotte, 550 F.3d 42, 105-06 (1st Cir. 2008). See also IMS Health, Inc. v. Mills, 616 F.3d 7, 48-49 (1st Cir. 2010). The Supreme Court granted certiorari in Sorrell v. IMS Health and heard oral arguments on April 26, 2011. Sorrell v. IMS Health, Inc., 131 S. Ct 857 (2011) (No. 10-779).

109 Berndt, Ernst R. et al., Information, Marketing, and Pricing in the U.S. Antiulcer Drug Market, 85 Am. Econ. Rev. 100, 104 (1995)Google ScholarPubMed (“We find that marketing information stocks positively affect sales, that the sales elasticity is largest for detailing, followed by journal pages of advertising, and is smallest for direct-to-consumer advertising.”).

110 Lurie, Nicole et al., Pharmaceutical Representatives in Academic Medical Centers, 5 J. Gen. Internal Med. 240, 240 (1990)CrossRefGoogle ScholarPubMed (“Independent predictors of faculty change in practice were brief or extended conversations and free meals.”).

111 Avorn, Jerry et al., Scientific Versus Commercial Sources of Influence on the Prescribing Behavior of Physicians, 73 Am. J. Med. 4, 7 (1982)CrossRefGoogle ScholarPubMed (“This predominance of commercial rather than scientific sources of drug information represents a problematic area in health care delivery.”).

112 See Ziegler, Michael G. et al., The Accuracy of Drug Information from Pharmaceutical Sales Representatives, 273 JAMA 1296, 1297 (1995)CrossRefGoogle ScholarPubMed (“Eighty-five percent of residents said pharmaceutical representatives provided useful information . . . .”).

113 See generally Fugh-Berman, Adriane & Ahari, Shahram, Following the Script: How Drug Reps Make Friends and Influence Doctors, 4 PLoS Med. 621 (2007)CrossRefGoogle ScholarPubMed (describing numerous tactics employed by one author in his previous job as a pharmaceutical sales representative).

114 New drugs are overwhelmingly more likely than older drugs to be updated with black box warnings or other important safety information. See Lasser, Karen E. et al., Timing of New Black Box Warnings and Withdrawals for Prescription Medications, 287 JAMA 2215, 2215 (2002)CrossRefGoogle ScholarPubMed (finding “half of [major changes to drug labeling] occurred within 7 years of drug introduction; half of the withdrawals occurred within 2 years”). There is also an efficacy issue. Because pharmaceutical promotion involves the newest drugs produced, the drugs most commonly the subject of the detailers' messages tend to be agents developed on the heels of a well-known successful agent that offer no substantial additional clinical benefits. For example, Loratadine (Claritin) was an antihistamine approved for seasonal allergies. As Claritin reached the end of its market exclusivity, Schering-Plough received a patent on a new antihistamine, desloratadine (Clarinex), which is the chemical structure that loratadine turns into when it is metabolized by the liver. Schering-Plough also specifically tested desloratadine to treat “in-door” allergies (such specific testing was never done for Claritin) and received approval from the FDA for this indication—even though it would be expected to work similarly well to loratadine in these situations, since they are essentially the same product.

115 See Bombardier, Claire et al., Comparison of Upper Gastrointestinal Toxicity of Rofecoxib and Naproxen in Patients with Rheumatoid Arthritis, 343 New Eng. J. Med. 1520, 1522 (2000)CrossRefGoogle ScholarPubMed (“The relative risk of confirmed upper gastrointestinal events for patients in the rofecoxib group as compared with those in the naproxen group was 0.5 . . . .”).

116 Krumholz, Harlan M. et al., What Have We Learnt from Vioxx?, 334 Brit. Med. J. 120, 121 (2007)CrossRefGoogle ScholarPubMed (“The published cardiovascular risk was not accurate because three additional myocardial infarctions occurred in the rofecoxib group in the month after the researchers stopped counting cardiovascular events (none had occurred in the naproxen group). The potential harm was further minimized by a post hoc subgroup analysis based on ‘indication for aspirin prophylaxis'; had Merck included the three cases, the subgroup analysis would have shown an increased cardiovascular risk in both groups.”).

117 Kesselheim, Aaron S. & Avorn, Jerry, The Role of Litigation in Defining Drug Risks, 297 JAMA 308, 309 (2007)CrossRefGoogle ScholarPubMed (“The information came to the attention of the public through a subpoena 5 years after the article's publication, when rofecoxib was already off the market.”).

118 Cardarelli, Roberto et al., A Cross-Sectional Evidence-Based Review of Pharmaceutical Promotional Marketing Brochures and Their Underlying Studies: Is What They Tell Us Important and True?, 7 BMC Family Prac. 1, 4 (2006)Google Scholar (finding “published studies that were sponsored by pharmaceutical companies were four times more likely to have outcomes favoring the sponsor's product than were studies that had other types of sponsors”).

119 Fischer, Michael A. & Avorn, Jerry, Economic Implications of Evidence-Based Prescribing for Hypertension: Can Better Care Cost Less?, 291 JAMA 1850, 1854 (2004)CrossRefGoogle ScholarPubMed (“Adherence to established guidelines for treating hypertension would have resulted in considerable savings to the health care delivery system ($11.6 million per year, or nearly a quarter of program antihypertensive medication costs).”).

120 See, e.g., Fischer, Michael A. et al., Medicaid Prior-Authorization Programs and the Use of Cyclooxygenase-2 Inhibitors, 351 New Eng. J. Med. 2187, 2193 (2004)CrossRefGoogle ScholarPubMed (“The state Medicaid programs' use of prior-authorization policies represents one attempt to direct the use of costly medications to the patients who will benefit most from them. Our data suggest that such programs can substantially reduce the use of coxibs”); Tamblyn, Robin et al., Adverse Events Associated with Prescription Drug Cost-Sharing Among Poor and Elderly Persons, 285 JAMA 421, 424 (2001)CrossRefGoogle ScholarPubMed (“The introduction of the drug policy was followed by substantial and statistically significant reductions in the overall number of drugs used per day by both elderly persons . . . and adult welfare recipients”); Soumerai, Stephen, Unintended Outcomes of Medicaid Drug Cost-Containment Policies on the Chronically Mentally Ill, 64 J. Clinical Psych. 19, 19 (2003)Google ScholarPubMed (“Vulnerable populations are most likely to experience adverse effects from hastily-applied drug cost-containment policies.”).

121 Shrank, William H. et al., The Implications of Choice: Prescribing Generic or Preferred Pharmaceuticals Improves Medication Adherence for Chronic Conditions, 166 Archives Internal Med. 332, 335 (2006)CrossRefGoogle ScholarPubMed (“For patients enrolled in tiered pharmacy benefit systems, clinicians can influence long-term adherence by choosing wisely within a drug class and prescribing generic or preferred formulary agents when initiating chronic therapy.”).

122 See Silverman, Gabriel K. et al., Failure to Discount for Conflict of Interest When Evaluating Medical Literature: A Randomised Trial of Physicians, 36 J. Med. Ethics 265, 267 (2010)CrossRefGoogle ScholarPubMed (finding in one small randomized trial “information on conflict of interest had no significant effect on prescribing likelihood”).

123 See Daylain M. Cain et al., Coming Clean but Playing Dirtier: The Shortcomings of Disclosure as a Solution to Conflicts of Interest, in Conflicts of Interest 105, 105-25 (Don A. Moore et al. eds., 2005).

124 Mason, Marlys J. & Scammon, Debra L., Health Claims and Disclaimers: Extended Boundaries and Research Opportunities in Consumer Interpretation, 19 J. Pub. Pol’y & Mktg. 144, 146 (2000)Google Scholar (“This research suggests that the disclaimer may have little effect on purchase decisions, particularly for some consumer segments.”).

125 Morris, Charles A. & Avorn, Jerry, Internet Marketing of Herbal Products, 290 JAMA 1505, 1505 (2003)CrossRefGoogle ScholarPubMed (finding widespread promotion of non-prescription drugs on the Internet).

126 Moulton, Patricia L. et al., The Effect of Ginkgo Biloba on Memory in Healthy Male Volunteers, 73 Physiology & Behav. 659, 664 (2001)CrossRefGoogle ScholarPubMed (“A primary result of the present study is the complete absence of any effect of G. biloba on any of the memory measures.”).

127 Fong, Tse-Ling et al., Hepatotoxicity Due to Hydroxycut: A Case Series, 105 Am. J. Gastroenterology 1561, 1561 (2010)CrossRefGoogle ScholarPubMed (“Hydroxycut has been clearly implicated as a cause for severe liver injury that may lead to acute liver failure and death.”).

128 Ross, Joseph S. et al., Guest Authorship and Ghostwriting in Publications Related to Rofecoxib: A Case Study of Industry Documents from Rofecoxib Litigation, 299 JAMA 1800, 1805 (2008)CrossRefGoogle ScholarPubMed (“Documents also were found demonstrating that medical publishing companies played critical roles in overseeing the development, organization, and manuscript drafting of supplemental issues focused on rofecoxib for journals.”). See generally Gøtzsche, Peter C. et al., What Should Be Done to Tackle Ghostwriting in the Medical Literature?, 6 PLoS Med. 122 (2009)CrossRefGoogle ScholarPubMed (describing different viewpoints on handling ghostwriting policies in the medical literature).

129 Brody, Howard, Pharmaceutical Industry Financial Support for Medical Education: Benefit, or Undue Influence?, 37 J.L. Med. & Ethics 451, 453 (2009)Google ScholarPubMed (reviewing evidence that “physicians later purchase products seen at the meeting”).

130 Similar to the taxation concept would be a proposal to change Medicare rules to create varying levels of reimbursement based on the type of use: highest level for on-label use or if there is a pending sNDA; partial for certain off-label uses with uncertain evidence or where no evidence can be obtained; none for off-label uses with insufficient evidence of benefit. Such a model would mirror the current tiered formulary system in place for brand-name and generic drugs that has been successful in driving some patients towards use of certain therapies over others. See Huskamp, Haiden A. et al., The Impact of a National Prescription Drug Formulary on Prices, Market Share, and Spending: Lessons for Medicare?, 22 Health Aff. 149, 149 (2003)CrossRefGoogle ScholarPubMed (“We find that the VHA National Formulary was effective at shifting prescribing behavior toward the selected drugs, achieving sizable price reductions from manufacturers, and greatly decreasing drug spending.”). However, with this proposal there is again the potential for increasing financial burdens on patients. See Hodgkin, Dominic et al., The Effect of a Three-Tier Formulary on Antidepressant Utilization and Expenditures, 11 J. Mental Health Pol’y & Econ. 67, 67 (2008)Google ScholarPubMed (“[T]he intervention also resulted in cost-shifting from plan to enrollees, indicating some price-inelasticity.”).

131 See Kesselheim & Avorn, supra note 67, at 1730-31 (providing a patient safety rationale for limits on commercial speech related to marketing of pharmaceutical products); Haw, Camilla & Stubbs, Jean, Off-Label Use of Antipsychotics: Are We Mad?, 6 Expert Opinion Drug Safety 533, 533 (2007)CrossRefGoogle ScholarPubMed (“When prescribing off-label, the prescriber must carry out a careful risk assessment of the risks and benefits for the individual patient. They should also inform the patient that the prescription is off-label.”). See also Gillick, Muriel R., Controlling Off-Label Medication Use, 150 Annals Internal Med. 344, 347 (2009)CrossRefGoogle ScholarPubMed (“Yet another approach mandates obtaining informed consent from patients before prescribing a drug for an unapproved indication.”).

132 See, e.g., Troy, Daniel E. & Gottlieb, Scott, Pharmaceutical Promotion and First Amendment Rights, 359 New Eng. J. Med. 536, 536 (2008)Google ScholarPubMed (justifying reduced regulation of pharmaceutical marketing). See also Meadows, W.A. & Hollowell, B.D., ‘Off-label’ Drug Use: An FDA Regulatory Term, Not a Negative Implication of its Medical Use, 20 Int’l J. Impotence Res. 135, 144 (2008)Google Scholar (concluding “the FDA's approval process, which is not related to the practice of medicine, is simply irrelevant to the risks of a treatment plan or procedure”).

133 Aaron S. Kesselheim et al., supra note 15, at 3-4 (describing the parameters of broad classifications of off-label use, including use in different diseases, uses in different subtypes of the same disease, and use at different dose levels).

134 Maisel, William H., Medical Device Regulation: An Introduction for the Practicing Physician, 140 Annals Internal Med. 296, 297 (2004)CrossRefGoogle ScholarPubMed (describing the regulatory posture related to 510(k) devices).

135 Diana M. Zuckerman et al., Medical Device Recalls and the FDA Approval Process, Archives Internal Med. Online First, Feb. 14, 2011, at 1 (“Most medical devices recalled for life threatening or very serious hazards were originally cleared for market using the less stringent 510(k) process or were considered so low risk that they were exempt from review (78%).”).

136 New evidence about potential safety concerns related to the original approved use may also emerge. At any time, a manufacturer can change its approved label by adding warnings to it without first notifying the FDA and receiving approval to do so. The Code of Federal Regulations states that “the labeling must be revised to include a warning about a clinically significant hazard as soon as there is reasonable evidence of a causal association with a drug; a causal relationship need not have been definitively proved.” Specific Requirements on Content and Format of Labeling for Human Prescription Drug and Biological Products Described in § 201.56(b)(1), 21 C.F.R. § 210.57(e) (2010). The FDA then in due course reviews the safety-related label change. According to two former ex-FDA commissioners, Drs. Donald Kennedy and David Kessler, “‘Although the FDA might later disapprove of a [strengthened warning] label . . . the FDA's power to disapprove does not make the manufacturer's voluntarily strengthened label a violation of federal law.'” Brief for Donald Kennedy, M.D. & David A. Kessler, M.D. as Amici Curiae Supporting Respondent at 14 n.7, Wyeth v. Levine, 555 U.S. 555 (No. 06-1249) (quoting Tucker v. SmithKline Beecham Corp., No. 1:04-cv-01748, 2008 U.S. Dist. LEXIS 55919, at *8 (S.D. Ind. July 18, 2008)). To my knowledge, there has never been an occasion where a manufacturer has added a stronger warning to a label and the FDA has later rejected this move.

137 Christopher Lee, FDA Considers Easing Curbs on Drug Makers, Wash. Post, Dec. 1, 2007, at A4 (“[D]rug and medical device manufacturers could distribute unabridged reprints of peer-reviewed research from reputable medical journals as long as the articles were not written, edited or otherwise ‘significantly influenced' by the manufacturers or people with financial ties to them.”).

138 Curfman, Gregory D. et al., Expression of Concern Reaffirmed, 354 New Eng. J. Med. 1193, 1193 (2006)CrossRefGoogle ScholarPubMed (“The information we have indicates that the VIGOR article, because it did not contain relevant safety data available to the authors more than four months before publication, did not accurately reflect the potential for serious cardiovascular toxicity with rofecoxib”); Turner, Erick H. et al., Selective Publication of Antidepressant Trials and Its Influence on Apparent Efficacy, 358 New Eng. J. Med. 252, 256 (2008)CrossRefGoogle ScholarPubMed (“Not only were positive results more likely to be published, but studies that were not positive, in our opinion, were often published in a way that conveyed a positive outcome”); Ridker, Paul M. & Torres, Jose, Reported Outcomes in Major Cardiovascular Clinical Trials Funded By For-Profit and Not-For-Profit Organizations: 2000-2005, 295 JAMA 2270, 2272 (2006)CrossRefGoogle ScholarPubMed (“In this survey of 324 consecutive cardiovascular clinical trials published in JAMA, The Lancet, and the New England Journal of Medicine between 2000 and 2005, we found that those funded by for-profit organizations were significantly more likely to report positive findings than those funded by not-for-profit organizations”); Joseph S. Ross et al., supra note 128, at 1800 (documenting the practice of industry ghost-writing of articles related to rofecoxib)