Jeffrey K. Francer Vice President and Senior Counsel. May 1, 2014

Transcription

1 Jeffrey K. Francer Vice President and Senior Counsel May 1, 2014 Division of Dockets Management (HFA-305) Food and Drug Administration 5630 Fishers Lane, rm Rockville, MD Re: Revised Draft Guidance for Industry on Distributing Scientific and Medical Publications on Unapproved New Uses Recommended Practices, Docket No. FDA 2008 D 0053, 79 Fed. Reg (Mar. 3, 2014) Dear Sir or Madam: The Pharmaceutical Research and Manufacturers of America (PhRMA) appreciates the opportunity to submit these comments in response to FDA s Revised Draft Guidance for Industry on Distributing Scientific and Medical Publications on Unapproved New Uses (Draft Guidance). The Draft Guidance revises FDA s 2009 final guidance titled Good Reprint Practices for the Distribution of Medical Journal Articles and Medical or Scientific Reference Publications on Unapproved New Uses of Approved Drugs and Approved or Cleared Medical Devices (2009 Guidance). PhRMA is a voluntary, non-profit association that represents the country s leading pharmaceutical research and biotechnology companies. PhRMA members are dedicated to developing medicines that allow patients to live longer, healthier, and more productive lives. In 2013 alone, PhRMA s member companies invested an estimated $51.1 billion in the research and development of new medicines. PhRMA recognizes the importance of FDA s regulatory processes for approving new medicines and new indications for previously approved medicines. At the same time, we also recognize the critical need of patients for their healthcare professionals to be well informed about the benefits and risks of all available uses of medicines, including those uses that may not be approved by the FDA but are nevertheless medically accepted, supported by compendia or clinical practice guidelines, and/or generally reimbursed by major payers, including the Centers for Medicare & Medicaid Services. 1 Physicians must be able to exercise their independent medical judgment in determining the appropriate treatment option for their patients, including, when appropriate, to prescribe an FDA-approved drug for an unapproved use. Likewise, PhRMA believes that its members can serve an important public health role and advance the interests of patients by providing truthful, non-misleading educational information to healthcare professionals about their medicines. Any appropriate regulation by FDA in this area thus 1 In these comments, we refer to such uses as medically accepted alternative uses of approved medicines.

2 Page 2 requires careful balancing of multiple interests. Accordingly, we hope that FDA can provide a clear safe harbor, so that biopharmaceutical companies may participate meaningfully in important healthcare dialogs with other participants in the healthcare ecosystem about the medicines that companies research, develop, manufacture, and bring to patients. Introduction Because physicians can and frequently do prescribe approved drugs for unapproved uses, PhRMA commends FDA for its continued recognition of the value to health care professionals of truthful and non-misleading scientific or medical publications on unapproved new uses. Draft Guidance at 6. We are deeply concerned, however, that certain statements and omissions in the Draft Guidance including statements deleted from the 2009 Guidance could call into question whether FDA appropriately values communication about certain types of scientifically accurate, data-driven medical and scientific information, as well as the right of healthcare professionals to prescribe medicines for medically accepted alternative uses of approved medicines. We encourage FDA, in final guidance, to reaffirm, as it did in its 2009 Guidance, the benefit to patients of clinically appropriate off-label prescribing in medical practice today. PhRMA supports FDA s continued focus on providing concrete guidance regarding the types of disclosures and other steps manufacturers should take in order to disseminate information about unapproved uses without risking regulatory or even criminal enforcement. Yet, we respectfully submit that certain of FDA s recommended practices would unduly and impermissibly burden biopharmaceutical companies truthful and non-misleading communication with healthcare professionals and ultimately risk chilling the provision of timely, educational, and accurate information to healthcare professionals about certain unapproved uses, many of which are medically accepted and indeed even the standard of care for certain diseases. PhRMA believes that FDA s regulation of medical communications should conform with the First Amendment and adhere to principles intended to ensure that healthcare professionals may benefit from scientifically accurate, data-driven information from all sources including the companies that research and develop new medicines. Such high level principles, which we encourage FDA to adopt, include the following: All communication about medicines (including that of companies, payers, and the government) should be truthful and non-misleading in order to benefit patient care. Materials should be factually correct and should contain material benefit and risk information necessary for trained professionals to make informed treatment decisions. In order to enhance patient care, healthcare professionals deserve access to accurate information about the benefits and risks of all medicines available for treatment. Any limitations on healthcare communications should be related to patient risk based on factors including the approval status of the medicine, general medical acceptance of the treatment (e.g., appearance in compendia and/or clinical practice guidelines), and the level of scientific sophistication of the audience.

3 Page 3 Adequate disclosures regarding risks and the limitations of scientific understanding are preferable to prohibiting certain healthcare communications. Such disclosures can help ensure that medical communications are data-driven and transparent. Biopharmaceutical companies respect FDA s authoritative role in determining that medicines are safe and effective. Accordingly, companies recognize the need for incentives for sponsors to continue to seek supplemental indications for approved medicines and will work with FDA to create and maintain such incentives. Companies must be able to provide adequate directions for use of both approved and medically accepted alternative uses of approved medicines for patients. PhRMA continues to support FDA s effort to provide guidance on biopharmaceutical companies ability to share scientific and medical information with healthcare professionals. At the same time, we encourage FDA to take this opportunity to examine whether each of the best practices it recommends is narrowly tailored toward advancing the agency s public health mission without unnecessarily impeding truthful, non-misleading communication about patient treatment options or hampering scientific debate. I. FDA s Guidance Should Continue to Recognize the Fact that Unapproved Uses of FDA-Approved Medicines are Lawful and Often Reflect the Best Possible Medical Care for Patients Today, as in 2009 when FDA last issued guidance on this topic, prescribing FDAapproved drugs for unapproved uses is not only lawful, but often is the best (or only) course of treatment for specific patients. PhRMA therefore has significant concerns that several FDA statements and key omissions in the Draft Guidance could undermine the necessity of healthcare professionals decisions to prescribe medicines for medically accepted alternative uses to benefit their patients. These aspects of the Draft Guidance are especially troubling when compared to FDA s more robust endorsement of medically appropriate prescribing for unapproved uses in its 2009 Guidance on the same topic. FDA s 2009 Guidance unequivocally acknowledged the patient benefits of medically accepted alternative uses of approved medicines. The 2009 Guidance observed [o]nce a drug or medical device has been approved or cleared by FDA, generally, healthcare professionals may lawfully use or prescribe that product for uses or treatment regimens that are not included in the product s approved labeling. Id. at 3. FDA, in 2009, further recognized that [t]hese off-label uses or treatment regimens may be important and may even constitute a medically recognized standard of care. Id. These observations by FDA were far from novel even in Yet the 2 See More Information for Better Patient Care: Hearing on S Before the Senate Comm. on Labor and Human Resources, 104th Cong. (1996) (statement of William B. Schultz, then-fda Deputy Commissioner for Policy) ( Congress did not intend FDA to interfere with the practice of medicine. Thus, once a drug is approved for marketing, FDA does not generally regulate how, and for what uses, physicians prescribe the drug. A physician Footnote continued on next page

4 Page 4 Draft Guidance, without citing any evidence for FDA to change its opinion since 2009, unduly minimizes the importance to patients of physicians lawful ability to help patients by prescribing medicines for unapproved uses when clinically appropriate. In particular, the Draft Guidance asserts that [w]hile physicians may exercise their professional judgment to make individual patient care decisions, the public health is often not well served when those judgments rest on anecdotal experience or even preliminary scientific study too often, the promise of safety and effectiveness made by such sources has not been demonstrated when adequate and wellcontrolled studies are completed. Draft Guidance at 2. Similarly, the Draft Guidance omits FDA s unambiguous and accurate statement from the 2009 Guidance that unapproved uses, in some instances, constitute the medically-recognized standard of care Guidance at 3. 3 Nothing justifies these changes in FDA s treatment of clinically appropriate off-label prescribing that often serve as medically accepted standards of care that benefit patients. Despite the agency s apparent reluctance to acknowledge the significance or prevalence of prescribing for unapproved uses today, the fact remains that the Food, Drug, and Cosmetic Act, 21 U.S.C. 301 et seq. (FDCA), still does not limit the ability of physicians, exercising independent medical judgment, to prescribe FDA-approved drugs to any patient to treat any condition or disease. As the Supreme Court recognized more than a decade ago, off-label usage... is an accepted and necessary corollary of the FDA s mission to regulate in this area without directly interfering with the practice of medicine. Buckman Co. v. Plaintiffs Legal Comm., 531 U.S. 341, 350 (2001). A physician may prescribe a legal drug to serve any purpose that he or she deems appropriate, regardless of whether the drug has been approved for that use by the FDA. Wash. Legal Found. v. Henney, 202 F.3d 331, 333 (D.C. Cir. 2000); see also Nat l Insts. of Health, Nat l Cancer Inst., Q&A: Off-Label Drugs (Jan. 6, 2004) ( [O]nce the FDA approves a treatment, licensed physicians can prescribe it for any purpose they consider medically appropriate. ). The drug approval process for supplemental uses of medicines, while serving an important public health interest, simply cannot keep pace with all advances in medical practice. Footnote continued from previous page may prescribe a drug for uses or in treatment regimens or patient populations that are not listed in the FDA-approved labeling. ). 3 Even before FDA issued its 2009 Guidance, the Agency long had recognized that in certain circumstances, offlabel uses of approved products are appropriate, rational, and accepted medical practice. FDA knows that there are important off label uses of approved drugs. More Information for Better Patient Care: Hearing on S Before the Senate Comm. on Labor and Human Resources, 104th Cong. (1996) (statement of William B. Schultz, then- FDA Deputy Commissioner for Policy); see also Carol Scheman, Prescription Drug Marketing and Promotion An FDA Perspective, Address before the PMA Public Affairs Section, Mid-Year Meeting (Apr. 15, 1992) (recognizing the value of unapproved uses in ensuring that science and medicine move forward to benefit patients with intractable illness ). The National Cancer Institute likewise has observed that [f]requently the standard of care for a particular type or stage of cancer involves the off-label use of one or more drugs. Nat l Insts. of Health, Nat l Cancer Inst., Q&A: Off-Label Drugs (Jan. 6, 2004). This is, in part, because clinical experience may indicate that an off-label use of a drug is safer and more beneficial than any drug labeled for that disease. Gregory Conko, Hidden Truth: The Perils and Protections of Off-Label Drug and Medical Device Promotion, 21 Health Matrix: The Journal of Law and Medicine 149, 156 (2011).

5 Page 5 As a result, physician prescribing of an approved drug for an unapproved use is not only lawful, it is integral to the practice of medicine in the United States. As the American Medical Association and numerous others have recognized, [t]he prevalence and clinical importance of prescribing drugs for unlabeled uses are substantial. Joseph W. Cranston et al., Report of the Council on Scientific Affairs: Unlabeled Indications of Food and Drug Administration-Approved Drugs, 32 Drug Info. J. 1049, 1050 (1998). 4 Unapproved uses are not only widely accepted in the medical profession, they often are necessary for healthcare professionals to meet the standard of care in treating patients. 5 That standard can require doctors to prescribe a drug for an unapproved use where, as commonly occurs, FDA has not approved any drug to treat a patient s disease or condition. In other words, some off-label uses have gained such medical acceptance that doctors may commit malpractice if they fail to prescribe for the off-label use. Coleen Klasmeier & Martin Redish, Off-Label Prescription Advertising, the FDA and the First Amendment: A Study in the Values of Commercial Speech Protection, 37 Am. J. Law Med. 315, 318 (2011). Reflecting that unapproved uses often are clinically effective and medically necessary, federal law authorizes and, in some instances, requires the government to provide reimbursement for such uses. The Medicaid Rebate Act, for example, requires the Secretary of Health and Human Services to reimburse States, healthcare professionals, hospitals, and patients for any off-label use that is medically accepted. 42 U.S.C. 1396r-8(d)(1)(B)(i). Congress defined the phrase medically accepted to mean that either the FDA has approved the drug for 4 See also Dep t of Defense, TRICARE; Off-Label Uses of Devices; Partial List of Examples of Unproven Drugs, Devices, Medical Treatments, or Procedures, 77 Fed. Reg , (June 27, 2012) ( In general, good medical practice and the best interests of the patient require that physicians use legally available drugs, biologics, and devices... according to their best knowledge and judgment. ); AHFS Drug Information xiv (Am. Soc y of Health- Sys. Pharmacists ed., 2012) ( [A]ccepted medical practice (state-of-the-art) often includes drug use that is not included in FDA-approved labeling. ). 5 In addition to being lawful, prescribing for unapproved uses in furtherance of patient health and safety is still pervasive, particularly in certain fields of medicine such as oncology. Approximately 20% of all medical prescriptions are for unapproved uses. U.S. Dep t of Health & Human Servs., Agency for Healthcare Research and Quality, Developing Evidence-Based Research Priorities for Off-Label Drug Use, at ii (May 2009) ( Drug use for indications not approved by the Food and Drug Administration exceeds 20% of outpatient prescriptions. ); David C. Radley et al., Off-label Prescribing Among Office-Based Physicians, 166 Archives Internal Med. 1021, 1021 (2006). In some medical specialties, such as pediatrics and oncology, the majority of prescriptions are for off-label uses. The off-label use of drugs in oncology has been estimated to reach 50%, or even more. Paolo G. Casali, Editorial, The Off-Label Use of Drugs in Oncology: A Position Paper by the European Society for Medical Oncology (ESMO), 18 Annals Oncology 1923, 1923 (2007). Most cancer patients receive at least one drug for an unapproved use. U.S. Gen. Accounting Office, Program Evaluation & Methodology Div. No , Off-Label Drugs: Reimbursement Policies Constrain Physicians in their Choice of Cancer Therapies 13 (1991). Between 50% and 70% of prescriptions by pediatricians in the United States are for off-label uses. Nat l Task Force on CME Provider/Industry Collaboration, On-Label and Off-Label Usage of Prescription Medicines and Devices, and the Relationship to CME, Vol. 1, No. 3. And as many as half of prescriptions for cardiac and anticonvulsant medications are for off-label uses. Muriel R. Gillick, Controlling Off-Label Medical Use, 150 Ann. Intern. Med. 344 (2009).

6 Page 6 the prescribed use or, absent FDA approval, that the use is cited in one or more of three specified drug compendia: the American Hospital Formulary Service Drug Information, United States Pharmacopeia-Drug Information, or the DrugDex Information System. See id. 1396r-8(k)(6). The Medicaid Rebate Act also expressly requires the States to establish drug coverage based on its broader medical acceptance, in contrast to simply FDA approval. See id. 1396r-8(d)(4)(C). Likewise, the Medicare Part D prescription-drug benefit program covers unapproved uses that might not be either FDA-approved or compendia-listed. Id. 1395w-102(e); see also Layzer v. Leavitt, 770 F. Supp. 2d 579, (S.D.N.Y. 2011) (holding that another federal agency unlawfully refused to provide Part D coverage for off-label uses that were not FDA-approved or listed in any of the statutory compendia). Against this backdrop, FDA offers no explanation or justification for its decision to delete its previous recognition, contained in the agency s 2009 Guidance, of the necessity of prescribing medicines for unapproved uses when clinically appropriate for individual patients. PhRMA respectfully submits that the change, whether intentional or not, is unjustified and will not serve patients or healthcare professionals well. Accordingly, PhRMA requests that FDA revise its Draft Guidance to re-acknowledge explicitly the legality of medically accepted prescribing for unapproved uses when clinically appropriate for patients based on the judgment of their healthcare professionals. Thus, FDA should continue to recognize the potential benefits to patients of medically accepted alternative uses of approved medicines and return the relevant text it deleted from pages two and three of the 2009 Guidance regarding such benefits for patients. II. The Guidance Should Reaffirm FDA s Previous Recognition of the Importance of Educating Healthcare Professionals Regarding Medically Accepted Unapproved Uses of Approved Medicines Because of the widespread, medically accepted, and government-subsidized unapproved uses of numerous FDA-approved medicines, it is critical that healthcare professionals have access to accurate, comprehensive, and current information concerning unapproved uses. Any FDA guidance concerning the dissemination of information about unapproved uses should reflect this, without equivocation. Yet, again, there is a marked difference between the 2009 Guidance and the Draft Guidance regarding the importance of educating healthcare professionals about unapproved uses, with the Draft Guidance apparently giving only a qualified approval. FDA should revise its current draft to emphasize the importance to patient care of the ability of companies to provide healthcare professionals with truthful, non-misleading information, including information about approved uses that may fall outside of the approved labeling (e.g., pharmacoeconomic information) or medically-accepted alternative uses of approved medicines. In its 2009 Guidance, FDA unambiguously recognize[d]... the important public health and policy justification supporting dissemination of truthful and non-misleading medical journal articles and medical or scientific reference publications on unapproved uses of approved drugs and approved or cleared medical devices to healthcare professionals and healthcare entities Guidance at 3. FDA further explained, at that time, that public health may be advanced by

7 Page 7 healthcare professionals receipt of medical journal articles and medical or scientific reference publications on unapproved new uses of approved or cleared medical products that are truthful and not misleading. Id. Departing from these clear and important statements that dissemination of truthful and non-misleading scientific information about unapproved uses promotes the public health, FDA now equivocates, stating only: Although this draft guidance, like the 2009 guidance, recognizes the value to health care professionals of truthful and non-misleading scientific or medical publications on unapproved new uses, it also continues to recognize that this information is in no way a substitute for the FDA premarket approval process, which allows FDA to be proactive, rather than reactive, in protecting the public health from unsafe or ineffective medical products. Draft Guidance at 6-7. PhRMA supports the FDA premarket approval process for new medicines, but it is also vital that healthcare professionals and entities have access to the best available information about medically accepted alternative uses of approved medicines. FDA and others have long recognized this fundamental point, as well as manufacturers roles in providing such valuable information to healthcare professionals. More than two decades ago, FDA s then-associate Commissioner for Health Affairs explained: 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 L. Nightingale, Unlabeled Uses of Approved Drugs, 26 Drug Info. J. 141, 145 (1992). Researchers, scientists, and even the government impart such information to healthcare professionals and the public, regardless of whether double-blind randomized clinical trials have been conducted. As the National Cancer Institute has explained, [r]esearchers continually conduct studies to determine new uses for already marketed drugs and to find effective combinations of drugs for new indications. The results of these studies are published in peerreviewed medical journals. When a new treatment approach seems to produce better outcomes for patients, other doctors adopt it and it may become a new standard of care. Nat l Insts. of Health, Nat l Cancer Inst., Q&A: Off-Label Drugs (Jan. 6, 2004). Healthcare professionals, however, have finite amounts of time in which they must both treat patients and keep up with developments in their fields. It would be difficult, if not impossible, for physicians in most fields to stay abreast of all developments in the medical literature concerning all potential treatment options for their patients. In most cases, the manufacturer as the entity that researched and developed a given medicine will be a critical resource for such information regarding its product. Biopharmaceutical companies necessarily collect and retain an extensive amount of clinical information about their products both before and after approval in order to satisfy requirements for approval, post-approval safety monitoring, and often to evaluate or develop potential new medical uses. For this reason, manufacturers often may be best source of information regarding unapproved uses. Steven R. Salbu, Off-label Use, Prescription, and Marketing of FDA-Approved Drugs: An Assessment of Legislative and Regulatory Policy, 51 Fla. L. Rev. 181, (1999); Klasmeier & Redish, 37 Am. J. L. & Med. at Without information from manufacturers, physicians might

8 Page 8 overlook useful treatments for their patients or fail to optimize the benefits of those drugs they do employ off-label. The American Medical Association (AMA) and the American Psychiatric Association (APA) have issued position statements supporting the dissemination of truthful and nonmisleading information about unapproved uses by biopharmaceutical companies. AMA, H Patient Access to Treatments Prescribed by Their Physicians, available at ( Our AMA supports the dissemination of independently derived scientific information about unlabeled uses by manufacturers to physicians, if the independent information is provided in its entirety, is not edited or altered by the manufacturer, and is clearly distinguished from manufacturersponsored materials. ); APA, Patient Access to Treatments Prescribed by Their Physicians (July 2007) (same), available at APAOfficialDocumentsandRelated/PositionStatements/ aspx. FDA s final guidance, like its 2009 Guidance, likewise should recognize unequivocally that educating healthcare professionals about unapproved uses, including by way of scientific or medical publications, reference texts, and clinical practice guidelines provided by biopharmaceutical companies, promotes the public health. III. Consistent with the First Amendment, FDA s Guidance Should Encourage and Facilitate, Rather Than Overburden, Manufacturers Efforts to Provide Healthcare Professionals With Truthful, Non-Misleading Information About Medically Accepted Unapproved Uses of FDA-Approved Drugs The Constitution s protection of an open and robust exchange of ideas principles that are central to the meaning and purpose of the First Amendment limits FDA s ability to regulate scientific speech. PhRMA respectfully submits that FDA should give additional consideration to these First Amendment limitations in issuing final guidance regarding biopharmaceutical companies dissemination of scientific or medical publications to healthcare professionals. 6 6 The First Amendment protects works which, taken as a whole, have serious literary, artistic, political, or scientific value, regardless of whether the government or a majority of the people approve of the ideas these works represent. Miller v. California, 413 U.S. 15, 34 (1973). The First Amendment accordingly protects scientific expression and debate just as it protects political and artistic expression. Bd. of Trs. of Leland Stanford Jr. Univ. v. Sullivan, 773 F. Supp. 472, 474 (D.D.C. 1991). In other words, scientific speech reside[s] at the core of the First Amendment. Wash. Legal Found. v. Friedman, 13 F. Supp. 2d 51, 62 (D.D.C. 1998), order vacated as moot sub nom. Wash. Legal Found. v. Henney, 202 F.3d 331 (D.C. Cir. 2000). The Supreme Court has confirmed as much since FDA s publication of the 2009 Guidance. In Sorrell v. IMS Health Inc., 131 S. Ct (2011), the Court reaffirmed that [s]peech in aid of pharmaceutical marketing... is a form of expression protected by the Free Speech Clause of the First Amendment. Id. at The Court further observed that the First Amendment serves a particularly critical function in the fields of medicine and public health, where information can save lives. Id. at 2664.

9 Page 9 The dissemination of scientific or medical journal articles, reference texts, and clinical practice guidelines are paradigmatic examples of core First Amendment protected speech. Publication of clinical trial results is a necessary means to disseminate scientific information and serves as a primary means by which scientists, healthcare professionals, and other stakeholders learn about scientific developments. Biopharmaceutical companies truthful and non-misleading reporting of clinical trial results about unapproved uses in journal articles or reference texts, and off-label treatment recommendations in clinical practice guidelines, is therefore constitutionally protected. Overly restrictive FDA regulation of biopharmaceutical companies dissemination of scientific or medical publications not only harm patient interests in physician education, but also would be subject to heightened scrutiny under judicial review and would not survive that test, thus unnecessarily jeopardizing FDA s ability to regulate labeling and advertising. 7 Even analyzed under commercial speech doctrine, burdensome FDA restrictions on biopharmaceutical companies truthful and non-misleading speech about medically accepted unapproved uses would fail, because the balance required when evaluating such restrictions favors a free flow of truthful and non-misleading scientific information. 8 Thus, FDA should consider whether some of the practices specified in its Draft Guidance burden truthful and non-misleading speech about medically-accepted unapproved uses to a degree that would not withstand constitutional scrutiny. If information in scientific or medical publications is truthful and non-misleading, there is little if any conceivable justification for FDA to prohibit manufacturers from distributing the 7 In Sorrell v. IMS Health, the Supreme Court applied heightened scrutiny to strike down Vermont s content-based and speaker-based restrictions on speech by pharmaceutical companies. Any FDA restrictions on the dissemination of scientific or medical publications only by biopharmaceutical companies likewise would be speaker-based because other individuals and entities may make the same statements to the same audiences without running afoul of the law. And the restrictions would be content-based, because companies would be penalized for disseminating information that references physicians prescribing for unapproved uses. In other words, FDA would impose a burden based on the content of speech and the identity of the speaker. Sorrell, 131 S. Ct. at This leads to a virtual presumption of unconstitutionality. As the Sorrell Court noted, [i]n the ordinary course it is all but dispositive to conclude that a law is content-based and, in practice, viewpoint discriminatory. Id. at Following Sorrell, the Second Circuit in United States v. Caronia, 703 F.3d 149 (2d Cir. 2012), held that the First Amendment precludes a conviction for misbranding based on a pharmaceutical sales representative s truthful and non-misleading speech alone. 8 Courts have long expressed skepticism about regulation of mixed commercial and scientific speech. See, e.g., Wash. Legal Found. v. Friedman, 13 F. Supp. 2d at 62 ( The resolution of this question is not an easy one, as the communications present one of those complex mixtures of commercial and non-commercial elements. ). At a minimum, therefore, the government must establish that a restriction on commercial speech directly advances a substantial government interest that could not be served as well by a more limited restriction. Central Hudson Gas & Elec. Corp. v. Public Serv. Comm n, 447 U.S. 557 (1980). This standard offers significant protection, particularly insofar as it disfavors paternalistic regulations targeted against particular speakers or messages. See, e.g., Thompson v. Western States Med. Ctr., 535 U.S. 357 (2002) (striking down federal statute prohibiting pharmacy compounding advertising under Central Hudson commercial speech test); Virginia State Pharmacy Bd. v. Virginia Citizens Consumer Council, 425 U.S. 748 (1976) (striking down state statute prohibiting pharmacy advertising of prescription drug prices).

10 Page 10 information to healthcare professionals. It is difficult to envision how such a restriction on truthful and non-misleading speech could satisfy First Amendment scrutiny, particularly in light of Sorrell. The lynchpin of regulation in this area, therefore, must be that truthful and nonmisleading speech is protected and permissible. Conversely, companies should never be permitted to disseminate a scientific or medical publication that is false or misleading, id. at 8, 13, 17. Additional guidance from FDA would help clarify the definition of false or misleading information, which is not always intuitive with respect to communications to medically-trained professionals. Specifically, PhRMA suggests that FDA explain that false or misleading means speech that a reasonable person with the recipient s knowledge, training, and experience would determine contains a material misrepresentation, omission, or failure to disclose information. Similarly, a misrepresentation, omission, or failure to disclose should be deemed material only if, after considering its source, content, and context, a reasonable person with the recipient s knowledge, training, and experience would reasonably be expected to rely on the information misrepresented, omitted, or not disclosed in determining a course of action. Moreover, under any First Amendment analysis, FDA s ability to restrict companies speech is at its lowest ebb in the context of medically accepted unapproved uses. It is especially difficult to conceive any legitimate justification for FDA to restrict truthful and non-misleading speech when the unapproved use at issue is medically accepted, supported by citations in one or more of the statutory compendia, and/or supported by clinical practice guidelines published in the Agency For Healthcare Research and Quality National Guideline Clearinghouse or a similar repository. We hope that these factors will guide FDA s determination of best practices for biopharmaceutical companies disseminating scientific information to healthcare professionals, as well as FDA s own enforcement priorities in this area. Below, PhRMA offers specific suggestions for revisions that FDA should make to the Draft Guidance to safeguard biopharmaceutical companies First Amendment right to provide truthful and non-misleading information to healthcare professionals regarding medicallyaccepted unapproved uses. IV. Specific Suggestions for Guidance Consistent with the First Amendment PhRMA requests that FDA revise the Draft Guidance as discussed below in order to provide a clear safe harbor that will enhance the ability of biopharmaceutical companies to benefit patients by delivering scientifically accurate, data-driven information to healthcare professionals. We also believe that these revisions will help conform the Agency s guidance to First Amendment requirements without impeding the Agency s interests in protecting the public health.

11 Page 11 A. FDA Should Not Limit Scientific Communications Merely to Adequate and Well-Controlled Clinical Investigations FDA s guidance should recognize that healthcare professionals, and thus their patients, benefit from a wide range of scientific, pharmacoeconomic, and clinical information information that greatly exceeds the scope of scientific or medical journal articles that satisfy FDA s definition of adequate and well-controlled clinical investigations. Draft Guidance at 7. The adequate and well-controlled studies requirement contained in the Draft Guidance properly serves as FDA s regulatory standard regarding which studies ordinarily may serve as the basis for FDA approval of a new drug or a new use of an approved drug. Yet this standard is not a measure of whether information about uses of medicines is truthful or non-misleading, nor should it be. FDA does not have the legal authority, nor a public health-based justification, to impose this adequate and well-controlled studies limitation on companies dissemination of truthful scientific information published in peer-reviewed scientific or medical journals simply because the information references unapproved uses. By imposing the adequate and well-controlled studies standard, the Draft Guidance would effectively prohibit the dissemination of many types of important and useful scientific information, including certain pharmacoeconomic analyses, 9 meta-analyses, subpopulation analyses, and real world evidence and observational studies that describe significant uses, benefits, and risks of medicines that can improve the effectiveness and/or efficiency of patient care. FDA is restricting information that may be made available to healthcare professionals despite its potential clinical value to patients and the fact that such a broad restriction would sweep in all sorts of scientifically important, truthful, and non-misleading communications. Healthcare professionals and patients can benefit from a more free-flowing exchange of timely, truthful, and scientifically accurate medical information. In addition, we note that Congress, in the Food and Drug Administration Amendments Act (FDAAA), has already required companies to report publically clinical trial results of a much wider range of studies for approved drugs than would be allowable under FDA s Draft Guidance. See 42 U.S.C. 282(j). PhRMA therefore recommends eliminating FDA s recommendation that articles or reference publications address only adequate and well-controlled clinical investigations. At a minimum, FDA s final guidance should include the Agency s statement in the 2009 Guidance that appropriate information can include historically controlled studies, pharmacokinetic (PK) and pharmacodynamic (PD) studies, and meta-analyses if they are testing a specific clinical hypothesis Guidance at 4. Further, FDA should include a statement that reports of investigations may be considered truthful and non-misleading even if they do not meet FDA s approval criteria as set forth in 21 C.F.R , through mechanisms such as proper qualification of data and disclaimers (e.g., disclosure of the number of trial participants, 9 We note that Congress expressly permitted the communication of pharmacoeconomic information about medicines based on competent and reliable analyses, not merely adequate and well controlled investigations. PhRMA is re-submitting its 2012 White Paper on the development of reasonable standards for communication of pharmacoeconomic information and requests that FDA incorporate such standards in this or a separate guidance.

12 Page 12 statistical significance, and other information that trained professionals may utilize to evaluate the quality of scientific and medical research findings). B. FDA Should Require Disclosure of Potential Conflicts or Biases Rather Than Prohibiting Truthful, Non-Misleading Scientific Communication FDA should not prohibit manufacturers from disseminating scientific or medical journal articles merely on the ground that such articles may be edited or significantly influenced by a drug or device manufacturer or any individuals having a financial relationship with the manufacturer or articles [w]ritten, edited, excerpted, or published specifically for, or at the request of, a drug or device manufacturer. (Draft Guidance at 9). These prohibitions could interfere with the dissemination of important company-sponsored research, potentially including the peer-reviewed summaries of the very Phase III pivotal trials upon which FDA bases its own approval decisions. FDA s restrictions on such communications are both unwarranted and unproductive. If the government disfavors dissemination of such scientific or medical journal articles, the remedy to be applied is more speech, not enforced silence. United States v. Alvarez, 132 S. Ct. 2537, 2550 (2012) (quoting Whitney v. California, 274 U.S. 357, 377 (1927) (Brandeis, J., concurring)); see also Sorrell, 131 S. Ct. at 2671 ( Vermont may be displeased that detailers who use prescriber-identifying information are effective in promoting brand-name drugs. The State can express that view through its own speech. ). It would therefore be sufficient for FDA to require, as the Draft Guidance already does, that manufacturers prominently disclose any potential conflicts or biases, including [a]ny person known to the manufacturer who has provided funding for the study and [a]ny author known to the manufacturer as having a financial interest in the manufacturer or in a product of the manufacturer that is included in the journal article, or who is receiving compensation from the manufacturer, along with the affiliation of the author, to the extent known by the manufacturer, and the nature and amount of any such financial interest of the author or compensation received by the author from the manufacturer. Id. at 10. Often, such information is already disclosed by medical journals, and healthcare professionals are able to evaluate this information accordingly. As stated above, such disclosure requirements are more narrowly tailored than outright censorship of truthful and non-misleading speech. See John Doe No. 1 v. Reed, 561 U.S. 186, 130 S. Ct. 2811, 2818 (2010) ( Disclosure requirements may burden the ability to speak, but they do not prevent anyone from speaking. ) (alterations and internal quotation marks omitted). Accordingly, FDA should remove the limitations in the Draft Guidance on the dissemination of articles or texts merely on the ground that such articles may be (i) edited or significantly influenced by a drug or device manufacturer or any individuals having a financial relationship with the manufacturer. or are (ii) [w]ritten, edited, excerpted, or published specifically for, or at the request of, a drug or device manufacturer. Draft Guidance at 9. Such interests should be disclosed as an alternative to FDA s blanket prohibition on scientific communication about research sponsored or influenced by biopharmaceutical companies.

13 Page 13 C. Distribution at Scientific Conferences FDA does not provide adequate justification to require that, while reprints may be distributed at medical or scientific conferences in settings appropriate for scientific exchange, reprints should not be distributed in promotional exhibit halls or during promotional speakers programs. Draft Guidance at 8; see also id. at 15 ( Similarly, while a CPG may be distributed at medical or scientific conferences in settings appropriate for scientific exchange, the CPG should not be distributed in promotional exhibit halls or during promotional speakers programs. ). If a scientific or medical journal article or clinical practice guideline is truthful and nonmisleading already a prerequisite for companies to lawfully disseminate it there is no reasoned basis for prohibiting manufacturers from distributing it during one part of a conference, but not another part of the same conference. This sort of restriction is decidedly arbitrary and is not narrowly tailored to protect either the public health or the integrity of the drug approval process. Accordingly, FDA should delete these restrictions in the final guidance. D. Reports of Healthy Volunteer Studies In providing guidance on appropriate scientific and medical communication eligible for dissemination under the Draft Guidance, there is no reason for FDA categorically to rule out distribution of reports of healthy volunteer studies published in scientific or medical journals. Draft Guidance at 10. Such reports can provide truthful and non-misleading information that would benefit a healthcare professional s understanding of a potential unapproved treatment option for patients. Indeed, FDA requires and reviews Phase 1 clinical studies as evidence of a drug s safety as part of the agency s own approval process; hence there is no compelling rationale for FDA to prohibit manufacturers from communicating such results from peerreviewed medical journals. Thus, we urge FDA to reconsider and delete its categorical exclusion of these types of scientific and medical communications from the safe harbor proposed in the Draft Guidance. E. Clinical Practice Guidelines PhRMA supports FDA s addition of best practices with respect to companies dissemination of clinical practice guidelines (CPGs); however, the Agency s proposal to import trustworthiness criteria developed by the Institute of Medicine (IOM) into a regulatory context is not appropriate. PhRMA appreciates the substance of the IOM s trustworthiness criteria and guidance; yet as the Draft Guidance acknowledges, Congress solicited the IOM to undertake a study that focused on the best methods used in developing [CPGs] in order to ensure that organizations developing such guidelines have information on approaches that are objective, scientifically valid, and consistent. Draft Guidance at 14 (quoting Pub. L. No , 122 Stat. 2595) (emphasis added). IOM s study was not directed to establishing best practices for biopharmaceutical companies, nor was it designed to produce regulatory standards for those companies dissemination of CPGs to healthcare professionals. PhRMA accordingly questions

14 Page 14 whether it is appropriate simply to borrow IOM s trustworthiness criteria for organizations involved in developing CPGs. We are especially concerned that a recent analysis in the Journal of Clinical Oncology comparing the IOM guidelines to current oncology CPGs used by physicians concluded that [t]he vast majority of oncology CPGs fail to meet the IOM standards for trustworthy guidelines. 10 Moreover, of the four leading causes of cancer-related mortality in the United States (lung, breast, prostate, and colorectal cancers) published between January 2005 and December 2010, the analysis found that [n]o CPG fully met all the IOM standards. Thus, while the IOM guidelines may serve as an important aspirational goal for CPG authors, it is far from clear that the standards are appropriate as an FDA regulatory standard. If a CPG is truthful and non-misleading, FDA lacks both the authority and a legitimate justification to restrict its dissemination solely on the ground that the CPG does not meet an otherwise unrelated standard for trustworthiness. Therefore, PhRMA believes that FDA should establish its own guidance for determining that CPG s are truthful and non-misleading. F. FDA Should Acknowledge Modern Information Dissemination Methods PhRMA is concerned that FDA s draft guidance requires certain permanently affixed statement[s] when articles today are likely to be transmitted by electronic media. (See Draft Guidance at 9, 12). FDA should provide guidance regarding how such statements may be provided when articles are distributed electronically. PhRMA suggests that such statements could be provided in an while also providing a link to or image of the journal article. V. Conclusion PhRMA and its member companies commend FDA for addressing the important issue of biopharmaceutical companies dissemination of scientific or medical publications to healthcare professionals. A free flow of truthful, non-misleading scientific communication can be expected to benefit patients through the education of their healthcare professionals. We continue to support the agency s efforts to provide a clear safe harbor regarding best practices for doing so without risking enforcement action especially for medically accepted alternative uses of approved medicines. PhRMA believes that appropriate revision of the draft guidance can enhance patient care through dissemination of scientifically accurate and data-driven information to healthcare professionals. Yet FDA s proposed restrictions on such scientific and medical communications should conform to the First Amendment and should be narrowly tailored in order to maintain healthy scientific debate and exchange of treatment information for the benefit of patients. 10 Reames BN, Krell RW, Ponto SN, et al. (2013) Critical evaluation of oncology clinical practice guidelines. J Clin Oncol 31:

15 Page 15 We appreciate the opportunity to submit these comments and would be happy to work with the agency to enhance the guidance in a manner that maximizes the free flow of scientifically accurate, data-driven information to healthcare professionals for the purpose of benefiting patients. Sincerely, Jeffrey K. Francer Vice President and Senior Counsel