Off-Label Communications and the Public Health Presentation to the Pharmaceutical Compliance Forum November 8, 2007

1. Off-Label Communications and the Public HealthPresentation to the Pharmaceutical Compliance ForumNovember 8, 2007 Paul E. Kalb, M.D., J.D. With appreciation for the contributions of Joan McPhee and Alan Bennett of Ropes & Gray and Dan Troy of Sidley Austin

2. Overview • Introduction • Off-Label Prescribing is Lawful, Common and Vitally Important to the Practice of Medicine • Many Government Policies and Practices Encourage Off-Label Prescribing • Open Communication of Clinical Trial Data is Essential to Public Health • Criminalizing the Dissemination of Truthful, Non-Misleading Scientific Data Threatens Public Health

3. 1. Introduction

4. Disconnect Between FDA-Approved Labelingand State of the Art Medical Practice • FDA-Approved Labeling of Drug Products Often Represents an Incomplete or Even Inaccurate Picture of the Current State of Medical Knowledge. “Science moves faster than the FDA.” Peter Barton Hutt, former FDA General Counsel FDA Seeks to Add Drugs’ New Uses to Labels, Washington Post, Mar. 29, 1994

5. Disconnect Between FDA-Approved Labelingand State of the Art Medical Practice • Many of the most beneficial uses for approved drugs are discovered in the post-FDA approval stage. • There is often a substantial time lag between scientific discoveries and FDA approval: • FDA approval of supplemental drug applications takes an average of more than two years • By the time of approval for a new use of a drug, two-thirds of medical journal articles regarding that use have already been published • New uses are recognized in U.S. Pharmacopoeia – Drug Information an average of 2½ years before FDA approval

6. Disconnect Between FDA-Approved Labelingand State of the Art Medical Practice • Many medically accepted off-label uses never become FDA-approved uses • There is frequently no rational economic incentive to seek supplemental approval for new uses late in a drug’s patent life • For certain diseases, it may be difficult, if not impossible, to find patients willing to participate in the large, randomized clinical trials required to obtain FDA approval for a new use

7. 2. Off-Label Prescribing is Lawful, Common, and Vitally Important to the Practice of Medicine

8. Off-Label Prescribing is Lawful, Common and Vitally Important to the Practice of Medicine • Physicians may lawfully prescribe FDA-approved drugs for any use consistent with available scientific data and appropriate medical practice “[A] physician may, as part of the practice of medicine, lawfully prescribe a different dosage for his patient, or may otherwise vary the conditions of use from those approved in the package insert.” 37 Fed. Reg. 16503 Aug. 15, 1972

9. Off-Label Prescribing is Lawful, Common and Vitally Important to the Practice of Medicine • The FDA has no jurisdiction over the practice of medicine: “FDA does not have the authority [under the FDCA provisions] to control decisions made by qualified healthcare practitioners to prescribe products for conditions other than those described in FDA-approved professional labeling, or to otherwise regulate medical or surgical practice.” FDA Guidance for Industry on Development of Risk Minimization Action Plans, March 2005 “The physician is responsible for making the final judgment as to which, if any, of the available drugs his patient will receive in the light of the information contained in their labeling and other adequate scientific data available to him.” 37 Fed. Reg. 16504 Aug. 15, 1972

10. Off-Label Prescribing is Lawful, Common and Vitally Important to the Practice of Medicine • DOJ has affirmed that the FDA has no jurisdiction over the practice of medicine: “DoJ recognizes that once a drug has been approved by FDA for a medical condition, a health care practitioner may lawfully prescribe the drug for any use, regardless of whether FDA has determined that drug to be safe and effective for that use.” Assistant US Attorney General Peter Keisler, November, 2004

11. Off-Label Prescribing is Lawful, Common and Vitally Important to the Practice of Medicine • Prescribing drugs off-label is extremely common: How often do you prescribe drugs for off-label indications? More than 40% of the time 9% 30% - 40% of the time 12% 20% - 30% of the time 17% 10% - 20% of the time 19% 5% - 10% of the time 18% Less than 5% of the time 18% Don’t know/not sure 7% Daniel Klein, Alexander Tabarrok,Do Off-Label Practices Argue Against FDA Efficacy Requirements?,Independent Institute, April 16, 2003

12. Off-Label Prescribing is Lawful, Common and Vitally Important to the Practice of Medicine • Off-label prescribing is pervasive in the practice of oncology: • 60% of oncologists report that they frequently prescribe medications off-label • More than half of all cancer patients have received an anti-cancer drug for an off-label use • Nearly every type of cancer is treated with off-label regimens • Roughly 95% of all oncology drugs are used off-label The Rationale for Off-Label Prescriptions, 12(3) Johns Hopkins Medical Letter: Health After 50 (May 2000); General Accounting Office, Report to the Chairman, Comm. On Labor and Human Resources, U.S. Senate, Off-Label Drugs: Reimbursement Policies Constrain Physicians in Their Choice of Cancer Therapies 20, 27 (1991); American Society of Clinical Oncology Daily News (May 14, 2001).

13. Off-Label Prescribing is Lawful, Common and Vitally Important to the Practice of Medicine • The need to address the risk of not treating patients leads to extensive off-label prescribing in oncology: “The labeling of anticancer products frequently presents an incomplete or even inaccurate picture of the current state of medical knowledge. For virtually every cancer drug, appropriate medical dosage differs from the terms on the product labeling.” John R. Durant, M.D., Executive Vice President, American Society of Clinical Oncology, 1998 “The off-label uses of approved drugs have been an important tool for advancing the treatment of cancer.” American Society of Clinical Oncology, 2003 “[I]n some cases, if you didn’t use the drug in the off-label way, you’d be guilty of malpractice.” M. Roy Schwarz, Vice President for Science and Education, American Medical Association

14. Off-Label Prescribing is Lawful, Common and Vitally Important to the Practice of Medicine • Lack of pediatric indications on drug labels leads to off-label prescribing: • According to FDA estimates, nearly 80% of all drugs prescribed for children are prescribed off-label “Because most of the drugs currently marketed for administration by prescription do not have pediatric dosing information as part of the label, clinicians are faced with the dilemma of either using drugs without much information to support them or depriving their patients of potentially effective and sometimes lifesaving therapy.” American Academy of Pediatrics, Off Label Uses of Drugs in Children, September 1999 • Jenette Restivo, Pediatric Drug Testing Enters Infancy Nature Medicine 9(6), June 2003, at 631

15. Off-Label Prescribing is Lawful, Common and Vitally Important to the Practice of Medicine • Off-label prescribing is also common in psychiatry: • One study found high percentages of off-label prescriptions in the psychiatric field: • 75% of anti-seizure medications • 66% of antipsychotic medications • 25% of antidepressant medications • Chain Drug Review, 48(1), Nov. 24, 2003

16. Off-Label Prescribing is Lawful, Common and Vitally Important to the Practice of Medicine • Off-label prescribing is common in psychiatry for numerous reasons: • Patients are often treated based on their symptoms rather than a specific diagnosis • Psychiatry patients often have disorders for which no drug has an indication • Even when a drug does have an indication for a particular disorder, patients often fall outside the labeled age or demographic group • Patients often fail to respond to labeled products, and experimentation and adaptation is necessary • Off-label prescriptions are often necessary to address adverse side effects associated with many psychiatric drugs

17. Off-Label Prescribing is Lawful, Common and Vitally Important to the Practice of Medicine • The FDA has recognized that off-label prescribing is necessary and valuable in the practice of medicine: “FDA recognizes that. . . off-label uses of approved products are appropriate, rational and accepted medical practice.” “FDA knows that there are important off label uses of approved drugs.” William B. Schultz, FDA Deputy Commissioner of Policy (1996, 2004)

18. Off-Label Prescribing is Lawful, Common and Vitally Important to the Practice of Medicine • FDA recognizes off-label usage may be the standard of care: • FDA’s Oncologic Drugs Advisory Committee (ODAC) rejected accelerated approval of Marqibo in December 2004 • Cited Rituxan as an available therapy, recognizing the widespread off-label use of Rituxan in the treatment of both front-line and refractory aggressive Non-Hodgkin's Lymphoma

19. “The government has not chosen to ban the prescription of drugs for off-label uses. It has not chosen to prohibit manufacturers from profiting from off-label prescriptions. It has not chosen to impose a fine or other pecuniary penalty on manufacturers for failure to seek supplemental applications, nor has it chosen to more stringently enforce its statutory authority to prosecute misbranding.” “Off-label use is widespread in the medical community and often is essential to giving patients optimal medical care . . . which medical ethics, FDA, and most courts recognize.” Buckman Co. v. Plaintiffs’ Legal Committee, 531 U.S. at 351 n.5 Buckman Co. v. Plaintiffs’ Legal Committee, 531 U.S. 341, 350 (2001) “Promotion of off-label uses does not promote unlawful activity because off-label use of drugs and devices by physicians is not unlawful.” Washington Legal Foundation v. Henney 56 F. Supp. 2d 81, [201] (D.D.C. 1999) United States v. Caputo, 288 F. Supp. 2d 912 (N.D. Ill. 2003) Off-label use of medical devices “is an accepted and necessary corollary of the FDA’s mission to regulate in this area without directly interfering with the practice of medicine.” Off-Label Prescribing is Lawful, Common and Vitally Important to the Practice of Medicine • The courts recognize the value of off-label uses to the proper practice of medicine:

20. Off-Label Prescribing is Lawful, Common and Vitally Important to the Practice of Medicine • The AMA has also affirmed the importance of off-label prescribing: “The prevalence and clinical importance of prescribing drugs for unlabeled uses are substantial…. Thus, the prescribing of drugs for unlabeled uses is often necessary for optimal patient care.” 1997 AMA Annual Meeting “The AMA affirms that a physician may lawfully use an FDA-approved drug for an unlabeled indication when such use is based upon sound scientific evidence and sound medical opinion.” AMA Policy 120.988 “Up-to-date, clinically appropriate medical practice at times requires the use of pharmaceuticals for ‘off-label’ indications as distinct from the specific approved indication(s) from the US Food and Drug Administration. . .” AMA House of Delegates, Resolution 820, “Off-Label Use of Pharmaceuticals,” September 21, 2005

21. 3. Many Government Policies and Practices Encourage Off-Label Prescribing

22. Many Government Policies and Practices Encourage Off-Label Prescribing • The Government supports the appropriate off-label usage of oncology drugs: “Off-label use of drugs is widespread in cancer treatment for several reasons. … Some cancer drugs are found to be effective against a variety of tumor types. … Cancer chemotherapy often involves the use of multiple drugs. … Cancer treatment is always evolving.” National Cancer Institute, Q&A Off-Label Drugs, posted December 31, 1999

23. Many Government Policies and Practices Encourage Off-Label Prescribing • The National Cancer Institute recognized off-label indications of Rituxan as standard of care • Front Line Aggressive Adult Non-Hodgkin’s Lymphoma: “Standard treatment options: … 1. CHOP plus rituximab” • Indolent, Noncontiguous Stage II/III/IV Adult Non-Hodgkin’s Lymphoma: “Standard treatment options: … 1. Rituximab may be considered as first line therapy” • Stage I, II, III, and IV Chronic Lymphocytic Leukemia: “Treatment options: … 2. Rituximab, and anti-CD20 monoclonal antibody.” National Cancer Institute website, www.cancer.gov

24. Many Government Policies and Practices Encourage Off-Label Prescribing “The publication of results from the Multiple Outcomes of Raloxifene Evaluation, or MORE trial, which show that the osteoporosis prevention drug raloxifene (Evista®) reduced the incidence of breast cancer in postmenopausal women with osteoporosis, brings additional peer-reviewed data to the body of evidence that supports the rationale for the Study of Tamoxifen and Raloxifene (STAR).”

25. Many Government Policies and Practices Encourage Off-Label Prescribing • Government policy on use of antipsychotics in nursing homes validates off-label usage: • CMS State Operations Manual recognizes a number of antipsychotic drugs for use for residents without psychological issues • Recognizing use as “necessary to maintain or improve the residents functional status”

26. Many Government Policies and Practices Encourage Off-Label Prescribing Medicare State Operations Manual, Appendix PP at F329 42 C.F.R § 483.25

27. Many Government Policies and Practices Encourage Off-Label Prescribing • Medicare federal coverage policy: • Medicare policy guidance specifically includes, as eligible for coverage, off-label uses supported by recognized compendia or peer-reviewed medical journals The Social Security Act defines a “medically accepted indication” for use of a drug to be any FDA-approved use, as well as other uses if- the drug has been approved by the FDA, and (i) the use is supported by certain compendia; or (ii) the use is medically accepted based on supportive clinical evidence in certain peer- reviewed medical literature. Social Security Act § 1861(t)(1) “FDA approved drugs used for indications other than what is indicated on the official label may be covered under Medicare if the carrier determines the use to be medically accepted, taking into consideration the major drug compendia, authoritative medical literature and/or accepted standards of medical practice.” Medicare Benefit Policy Manual (CMS Pub. 100-2) Chapter 15 §50.4.2

28. Many Government Policies and Practices Encourage Off-Label Prescribing • Medicaid federal coverage policy: “The term ‘medically accepted indication’ means any use for a covered outpatient drug which is approved under the Federal Food, Drug, and Cosmetic Act, or the use of which is supported by one or more citations included or approved for inclusion in any of the compendia described in section (G)(1)(b)(i).” Social Security Act § 1927 (G)(1)(b)(i)

29. Many Government Policies and Practices Encourage Off-Label Prescribing • Edmonds v. Levine: • In federal court in Florida, plaintiffs seeking coverage for off-label uses on Neurontin challenged a state policy that to be "supported by” Drugdex compendium, the efficacy of a drug had to be demonstrated in two randomized, controlled clinical trials • Magistrate judge granted plaintiffs’ motion, and required reimbursement for 54 off-label uses of Neurontin “The court direct[s] the defendant to stop applying the ‘Neurontin Policy’ effective July 2004, and provide coverage for off-label uses of Neurontin which are cited in one of the Congressionally approved compendia.” Edmonds v. Levine, 2006 WL 453911, at *2 (S.D. Fla. 2006)

30. 4. Open Communication of Clinical Trial Data is Essential to Public Health

31. Open Communication of Clinical TrialData is Essential to Public Health • The FDA has acknowledged the importance of access to information regarding off-label uses: The “principle for the FDA is that the very latest information that can be of value to physicians, pharmacists, and patients must be made available as soon as possible. Frequently, unlabeled use information is extremely important.” Stuart J. Nightingale, FDA Associate Commissioner for Health Affairs, Unlabeled Uses of Approved Drugs, 26 Drug. Info. J. 141,145 (1992).

32. “Disseminating prompt, accurate information in usable formats to community health care providers and the public about cancer prevention and treatment advances is a critical step in the translation - the link between an intervention's development and its adoption in clinical practice." "To achieve the ultimate goal of dissemination - enabling individuals and organizations to adopt evidence-based approaches that will help reduce the risk and burden of cancer - specific education and communication needs of the public, health care professionals, and research community must be met.” President's Cancer Panel, 2004-2005 Annual Report, at 65. President's Cancer Panel, 2004-2005 Annual Report, at ix. “Simply put, we are not applying what we know – interventions demonstrated to be efficacious and validated through the clinical trials process – nearly well enough, quickly enough, or widely enough.” The National Cancer Program: Assessing Past, Charting the Future, 1999 Annual Report Failure to Communicate Clinical Trial Data is a Major Public Health Problem • President’s Cancer Panel affirms that the sharing of clinical information is important:

33. Open Communication of Clinical TrialData is Essential to Public Health • The AMA has affirmed the importance of access to accurate information regarding off-label uses: “It is imperative that physicians have access to accurate and unbiased information about unlabeled uses of prescription drugs.... Dissemination of independently derived scientific information about unlabeled uses by manufacturers to physicians can help physicians have access to the latest, scientifically credible information.” 1997 AMA Annual Meeting

34. Open Communication of Clinical TrialData is Essential to Public Health • Access to scientific information regarding off-label uses is of particular importance outside of urban areas of academic medical excellence: Physicians outside of major urban areas “have very little time to pursue information; therefore, information must be immediately accessible, concise, high quality, presynthesized, and up-to-date.” Dee and Blazek, Information Needs of the Rural Physician: A Descriptive Study, Bull Med Libr. Assoc 81(3), July 1993, at 263.

35. Open Communication of Clinical TrialData is Essential to Public Health “[I]t is well-documented that physicians rely upon the [pharmaceutical] industry for much of their drug information.” Spiller and Wymer, Physicians’ Perceptions and Uses of Commercial Drug Information Sources: An Examination of Pharmaceutical Marketing to Physicians, Health Marketing Quarterly Vol. 19(1) (2001), 94

36. Open Communication of Clinical TrialData is Essential to Public Health • 73% of the physicians surveyed in a 2001 study found information from pharmaceutical sales representatives to be useful to their practice: • 57% of physicians in the study found sales reps to be a “somewhat useful” source of information. • 16% of physicians found sales reps to be “extremely useful.” Spiller and Wymer, Physicians’ Perceptions and Uses of Commercial Drug Information Sources: An Examination of Pharmaceutical Marketing to Physicians, Health Marketing Quarterly Vol. 19(1) (2001), 96

37. Open Communication of Clinical TrialData is Essential to Public Health • Industry-wide movement towards sharing of clinical trial data, particularly after GSK NY settlement regarding full disclosure of clinical trial data: “This settlement holds GSK to a new standard of disclosure about studies concerning its drugs, a standard that helps to ensure that doctors and patients have access to all scientifically sound information so doctors can prescribe appropriate medication for their patients.” NY AG Elliott Spitzer

38. 5. Criminalizing the Dissemination of Truthful, Non-Misleading Scientific Data Threatens Public Health

39. Federal Prosecutors are Pursuing the Disseminationof Off-Label Information as Criminal and Civil Misconduct • Federal prosecutors are prosecuting off-label dissemination as a federal crime • Some cases have been resolved by criminal pleas and the payment of substantial fines • No adjudications on the merits • Numerous other cases are currently under investigation

40. Federal Prosecutors are Pursuing the Disseminationof Off-Label Information as Criminal and Civil Misconduct • In these cases and investigations, the government has pursued criminal off-label charges through two distinct legal theories under the Federal Food Drug and Cosmetic Act: • Misbranding “no adequate directions for use” 21 U.S.C. §§ 331(a), 352(f) • Unapproved new drug, 21 U.S.C. §§ 331(d), 355 • Neither theory of criminality requires false or misleading representations or other inherently wrongful conduct

41. Federal Prosecutors are Pursuing the Disseminationof Off-Label Information as Criminal and Civil Misconduct Off-label On-label Truthful, Non-Misleading Untruthful or Misleading “Early” or “emerging” data are not inherently misleading. Context is critical.

42. Federal Prosecutors are Pursuing the Disseminationof Off-Label Information as Criminal and Civil Misconduct • Criminal prosecution for the truthful, non-misleading off-label communications raises numerous concerns: • Statutory: • While false and misleading statements are expressly prohibited by the Food, Drug and Cosmetic Act, truthful, non-misleading statements are not, raising doubt as to whether the more general prohibition on introduction of goods into interstate commerce without “adequate directions” or introducing “new drugs” without FDA approval can be interpreted to prohibit truthful, non-misleading statements. • Constitutional: • There is serious doubt about whether the Government may criminalize the dissemination of truthful, non-misleading scientific information. • Policy: • Criminalizing truthful, non-misleading scientific speech carries the substantial risk of chilling investment in off-label research, dissemination of truthful, non-misleading off-label information, support for scientific meetings, and support for CME. • All of this negatively impacts public health.

43. Federal Prosecutors are Pursuing the Disseminationof Off-Label Information as Criminal and Civil Misconduct “[W]e need to ask whether or not it is helpful for attorneys that are part of the United States government to be criminalizing people who are conveying to doctors truthful, non misleading scientific information that, in many cases, the government’s own scientists are themselves developing. It seems to me that activities to criminalize the dissemination of truthful, non-misleading information about new uses for existing drugs, especially in fields marked by rapid medical advance like cancer, has the potential to greatly impede the ability of patients to access the latest therapies based on the most up-to-date medical evidence.” Scott Gottlieb, M.D., FDA Deputy Commissioner (December 2006)

44. Federal Prosecutors are Pursuing the Disseminationof Off-Label Information as Criminal and Civil Misconduct • The Government is also pursuing off-label promotion civilly, primarily under the False Claims Act • Legally uncertain and unsettled • Nonetheless, a substantial threat • Amplifies policy concerns about suppression of truthful, non-misleading scientific information

45. Solutions? • Continue to clarify the FDA rules distinguishing between impermissible off-label promotion and permissible scientific exchange. • Establish clear guidelines for investigation and prosecution of off-label cases. Ask: • Whether conduct conforms with FDA “safe harbor?” • Whether communications are truthful and non-misleading? • Whether patients are helped or harmed? • Whether FDA approved process has been undermined?

46. THE END