Worldwide: Off-Label Use: Current Position In The EU And US

INTRODUCTION

The terms of a licence to place a medicinal product on the market set out the approved conditions for use of that medicinal product, including the approved indications for use. However, while the licence controls how the licence holder can market its product, it does not regulate how healthcare professionals ("HCPs") prescribe the product. HCPs may decide to prescribe a medicinal product based on their experience and clinical judgment, regardless of its approved indications for use and the other conditions set out in the licence. This is known as off-label use, as the product is intentionally prescribed in circumstances that are outside the approved conditions set out in the product label. Examples include use of a medicinal product for a different indication, in another age group, dose or route to that approved by the regulatory authority.

Off-label use, and the extent to which information can be provided about such use, has become a hot topic in recent years, on both sides of the Atlantic. In the U.S., the focus has been on communications by licence holders of off-label indications for authorised products. In the EU, there have been controversies where governments or national healthcare systems have promoted off-label use for economic reasons where a more expensive approved alternative is available. The limits of communications regarding off-label use have been fought in the Courts in the EU and U.S., and legislative bodies are attempting to grapple with the question of how far a company, or a national healthcare system, can go to promote a product for an indication for which it has not been authorised.

This article sets out the current position in the EU and U.S., as well as some of the areas that will need to be clarified in the future.

CURRENT POSITION IN THE EU

The general rule is that a medicinal product may not be placed on the market unless a marketing authorisation has been granted by a competent regulatory authority which is satisfied that the criteria relating to quality, safety and efficacy are satisfactorily met.i The approved conditions of use are described in the Summary of Product Characteristics ("SmPC") which sets out the agreed position on how the product may be used safely and effectively. The marketing authorisation gives the holder the right to market the product within its terms, and the approved indications determine the uses for which it may be promoted. However, neither the marketing authorisation nor the legislation determine the circumstances in which a medicinal product may be prescribed; a doctor may choose to prescribe a product outside the terms of the marketing authorisation on the basis of his/her clinical judgment.

Article 5(1) of the Directive sets out an exemption to the requirements to have a marketing authorisation for the purposes of named patient supply. Under this exemption, a doctor may decide at his/her discretion and under his/her responsibility, to recommend or prescribe use of a medicinal product for the patients under his/ her care "to fulfil special needs", even if the medicine has not been granted a marketing authorisation. Member States are required to give effect to this provision through transposition into their domestic laws. In addition, article 83(1) of Regulation (EU) No 726/2004 creates an option allowing Member States to make available on a compassionate use basis, medicinal products which may be the subject of an application for an EU marketing authorisation under articles 3(1) and 3(2) of the same Regulation. Such compassionate use programmes are limited to patients with a chronically or seriously debilitating disease or whose disease is considered to be life-threatening, and who cannot be treated satisfactorily with an authorised medicinal product. The particular arrangements for such programmes are governed by individual Member State legislation, and the specific requirements may vary between Member States. While these provisions do not specifically apply to off-label use, and the Court of Justice of the European Union ("CJEU") has confirmed that "off-label prescribing is not prohibited, or even regulated, by EU law",ii these provisions are used, by analogy, to circumstances where a product is supplied outside the terms of its marketing authorisation. Recently, some Member States have also put in place programmes sanctioning off-label use, in circumstances where an alternative licensed product is available, because of cost considerations.

In terms of advertising and communication of off-label indications, article 87(2) of the Directive provides: "All parts of the advertising of a medicinal product must comply with the particulars listed in the [SmPC]." The proactive provision of information by a pharmaceutical company about an unauthorised use of a medicine is very likely to be seen as unlawful promotion. However, while the definition of advertising is very broad, it does not include responses to unsolicited requests for information, received by pharmaceutical companies in relation to their products, or the legitimate exchange of medical and scientific information during the development of a medicine, if such information is accurate, balanced and up-to-date. However, each one of these activities must be considered on a case-by-case basis, as the context in which such information is provided will be important in determining whether the activity is acceptable.

Current interest in off-label use has focused on the prescription and use of off-label products, especially where promoted by national authorities. In particular, the Italian and French authorities introduced cost-saving policies in 2014 to permit prescribing of bevacizumab (Avastin) for ophthalmic indications, particularly wet age-related macular degeneration ("AMD"), despite the availability of other medicinal products, including ranibizumab (Lucentis) and aflibercept (Eylea), authorised for intra-vitreal injection for the treatment of such conditions. Avastin and Lucentis/Eylea have a similar mechanism of action, but Avastin is indicated only for intravenous administration in oncology (for the treatment of colon, breast and kidney cancers).

Following the introduction of these controversial policies in Italy and France, the European Commission received a number of questions from Member States and other stakeholders in relation to the issues, and the associated legal and medical implications. In January 2015, EFPIA, EUCOPE and EuropaBio filed a complaint against the Italian law of May 2014 which provides for reimbursement of medicinal products used off-label even though a licensed alternative is available.iii A further complaint was issued in September 2015 in relation to an amendment to the French system, which allows the French medicines regulator to issue a temporary recommendation for use of a product in an unauthorised indication, for economic purposes, notwithstanding the existence of an authorised alternative treatment.iv

These complaints highlight the inconsistency between the strict regulatory process for authorisation of medicinal products, and the promotion by national authorities of unauthorised indications for products which have not been subject to those stringent requirements, for economic reasons. The position set out by EFPIA, EUCOPE and EuropaBio is also in line with a 2012 decision of the CJEU,v which considered the supply of unlicensed medicinal products under article 5(1) of Directive 2001/83/EC. In that case, the CJEU specially stated that financial considerations cannot, in themselves, lead to recognition of the existence of special needs capable of justifying the unlicensed use of a medicinal product in preference to a product with a marketing authorisation for the indication in question.

The policies in Italy and France have also resulted in litigation in the national courts. In Italy, in 2014, the antitrust authority fined Novartis and Roche over €180 million after concluding the companies had established a cartel aimed at preventing the off-label promotion of Avastin in order to foster the promotion of (on-label) Lucentis. In particular, it was found that the companies had agreed to portray the cheaper Avastin product as having certain safety issues compared to Lucentis because it was not authorised for use in AMD. The antitrust authority found that the companies had earned profits to the detriment of market efficiency, and this had impaired competition. Following a number of appeals, in June 2016, the Italian Council of State (the Administrative Supreme Court), issued – at the parties' request – a request for a preliminary ruling to the CJEU asking a number of questions about whether an agreement between Novartis and Roche to promote the sale of Lucentis breaches European antitrust rules; the decision of the CJEU is awaited.vi

Most recently, in February 2017, the Conseil d'Etat, the French Administrative Supreme Court, rejected a challenge by Novartis against the recommendation issued by the French authorities sanctioning the use of off-label Avastin in wet AMD, despite the availability of Lucentis.vii The Conseil d'Etat concluded that the provisions of the French Public Health Code were in line with EU law, as the case law of the CJEUviii shows that pursuant to article 5(1) of the Directive, an authorised medicinal product may, in certain circumstances, be used off-label, notably if its active ingredient is different from that of the product authorised for such indication, provided that the prescribing doctor deems it indispensable to use this medicine to meet the therapeutic needs of his patient.

European Commission Study

In 2013, the European Parliament adopted a resolution requesting the EMA to draw up a list of off-label medicines which were used despite the existence of an approved alternative, and to develop guidelines on off-label use. The Commission responded that such action was premature, and it would commission a study to understand better the scope and ramifications of the issue. The report of this study (the "Study")ix was ultimately published in February 2017 by the European Commission.

The Study provides a factual analysis of off-label use across the EU. This includes its legal framework, its prevalence (cited in the Study as around 20% of prescriptions), a description of its drivers and a review of the existing and potential policy tools that could be used to better regulate the practice. A review of literature and case law was performed, as well as consultation with a number of key stakeholders, including representatives from regulatory authorities, health technology assessment bodies, patients, HCPs, industry and experts.

The Study is said to cover the public health aspects related to off-label use, and the balance between the benefits and risks for patients. While the purpose of the Study was principally to describe the situation from a factual perspective, some sectors, particularly the industry, have been disappointed with the lack of recommendations provided, and in particular, the lack of consideration given to important issues such as off-label prescribing in the context of licensed alternatives and the promotion of off-label prescriptions for purely financial reasons. The widespread criticism of the policies of the authorities in Italy and France in relation to off-label prescribing, together with the fact that such policies have been supported by their respective courts, reflects uncertainty in this area and demonstrates an urgent need for clarification at EU level.

The drivers

The Study lists a number of reasons why off-label use is so prevalent in the EU:

  • Regulatory incentives: Directive 2001/83/EC provides for one additional year of marketing protection if a new indication is registered in the first eight years after an authorisation is granted, provided this new indication brings significant clinical benefit over existing therapies. However, this additional year of marketing protection provides only limited benefit, particularly as doctors may prescribe a product off-label even without a company investing in such new indications. Furthermore, generic competition, low prices for off-patent medicines, and increases in regulatory requirements mean there may be little incentive for a company to make such an investment.
  • Supply issues: Disruption in the manufacturing of a product or its withdrawal (for commercial or safety reasons) from the market can provoke a need for off-label use of a different product. Similarly, some products (or some indications) may be authorised in some Member States but not in others, or a product may be authorised but not made available, triggering the need for off-label prescribing of available products.
  • Lack of authorised alternatives: The prescriber may have no choice but to prescribe off-label in circumstances where particular patient groups were not included in the clinical trials and are therefore not reflected in the SmPC for particular products.
  • Cost: The most controversial drivers for off-label use are related to pricing and reimbursement. In this context, the Study recognises that pricing may be the reason for off-label use in those cases where the on-label product is more expensive than the off-label product and both are reimbursed. Further, there are circumstances where the off-label use of a product is reimbursed while use of the on-label product is not, leading to off-label prescribing despite the availability of the on-label product.x

The Policy Options

On the basis of these findings, the Study identifies a number of policy tools that could be used to better regulate off-label use:

  • Regulating off-label prescription for specific products Competent authorities might evaluate the risk-benefit profile of the medicine in its off-label use; only medicines with a favourable risk-benefit profile would be granted a permit to be prescribed off-label, as currently occurs in Hungary and France. In France, patients should be monitored through a protocol, and the marketing authorisation holder is required to collect safety and efficacy information, and to provide all available data to the regulatory authorities. Such systems serve to increase patient safety, and strengthen the prescriber's position with regards to liability. Their downside is that a refusal may be disadvantageous for individual patients, as off-label use may be prohibited, based on an evaluation of the average risk/benefit ratio across the population, rather than in an individual patient. The option also encounters reluctance from some companies and physicians due to the burden that these reporting obligations entail.
  • EU guidance to assist with development of national guidelines of off-label prescribing EU guidance could be provided to establish a common ground for national treatment guidelines in Member States. In fact, on 8 April 2017, the CPME (the Standing Committee of European Doctors) adopted a policy on off-label use.xi This sets out some best practice for prescribing a product off-label, including the fact that it should only take place where there is no alternative authorised treatment that would better serve patients' needs.
  • Treatment guidelines for specific products Off-label prescription could be regulated using protocols or professional standards prepared by the relevant professional bodies on specific off-label use, as is the case in the Netherlands. Such guidelines would provide information on the risk-benefit balance of the product, so prescribers and patients could make an informed decision.
  • Changes in data requirements Data, other than from industry-based randomised controlled trials, could be accepted as evidence for applications for authorisations; for example, by accepting monitoring data on efficacy and safety, real-world data from patient registries, or pharmacovigilance data. However, in order to ensure patient safety, it should be clear which quality standards apply for these data to be acceptable.
  • Incentives for pharmaceutical companies to register new indications The authorisation of new indications enhances patient safety and supports prescription by HCPs. Industry stakeholders argued that additional incentives should be added to the EU legal framework to reward the investment needed to develop new indications, although other stakeholders considered the current incentives (including those under the Paediatric Regulation and the Orphan Drug Regulation) to be sufficient.
  • Reimbursement measures Reimbursement systems could be amended to allow for off-label use, including: (i) reimbursing off-label use where a product is included in treatment guidelines; (ii) reimbursing off-label use for which there is no competitor on the market; and/or (iii) reimbursing off-label use where the off-label product is less expensive than its on-label competitor. The last option caused controversy among stakeholders. The authors of the Study noted the decision of the CJEU in European Commission v Poland,xii which confirmed that the exemption to the requirement for a medicinal product to be supplied in accordance with a marketing authorisation, under article 5 of Directive 2001/83/EC, cannot be applied for financial reasons only. They commented that:

    "[I]t can be debated whether allowing reimbursement of off-label use in case it is less expensive than its on-label competitor is (always) against the medical need of an individual patient. Moreover, medicinal products may become available to patients who otherwise would not have access to these medicines."

    The Study states that industry was opposed to this option, but does not present any analysis of its lack of consistency with the EU medicines regulatory framework.
  • Awareness campaigns HCPs and patients could be informed about off-label use via awareness campaigns. However, campaigns for HCPs were not considered useful, as needs differ per country and per specialism. Nor were they considered useful for patients, as off-label use is not relevant for a large majority of patients.

The European Commission now needs to consider the results of the Study, and how it will respond to the questions raised, and whether new legislation or guidance should be published.

CURRENT POSITION IN THE U.S.

In the U.S., when the Food and Drug Administration ("FDA") approves a new prescription drug or a new indication of a previously-approved prescription drug, FDA also approves the professional labelling for that drug, known as the "package insert" ("PI"). The Federal Food, Drug, and Cosmetic Act ("FDCA"), related FDA regulations, and FDA enforcement policy historically prohibited the manufacturer of a prescription drug from marketing or promoting that drug for any use other than the one approved by FDA and described in the approved PI.xiii The language of the relevant statutes and regulations do not explicitly prohibit off-label promotion. Nevertheless, FDA and the U.S. Department of Justice have used the statutory and regulatory definitions of "labelling" and "intended use" to prohibit proactive communications involving off-label uses.xiv A violation of the FDCA is a criminal act and the statute permits prosecution even where an individual or company has not acted with intent in the conventional sense.xv

By contrast, the FDCA prohibits FDA from regulating the independent practice of medicine under these and other FDCA provisions. HCPs commonly, and appropriately, prescribe unapproved uses of approved prescription drugs for their patients. Furthermore, these off-label uses are often endorsed by treatment guidelines, drug compendia, and other authoritative sources representing the standard of care. FDA has recognised that certain non-promotional communications to HCPs by companies about those off-label uses may be permissible when other controls are present.xvi But those advocating for allowing broader communications regarding off-label uses have noted that the narrow exceptions permitting such communication are insufficient to allow a full exchange of medical information that would benefit patient care. There are also concerns about the legal ramifications of communicating outside the narrow boundaries established by FDA, given the possibility of severe sanctions under the FDCA. On the other hand, there are concerns that FDA permission to freely disseminate information on off-label uses would undermine the incentives for companies to seek new and supplemental approvals for drugs already on the market.

For many years, industry has asked FDA to evaluate its policies and regulations and to update its position on manufacturer communications to better align with the modern healthcare system. The tension between FDA and industry have recently come to a head as a result of recent court decisions.

In recent years, the Courts have acknowledged that restrictions on the communication of truthful and non-misleading speech about medically accepted unapproved uses to HCPs violate manufacturers' First Amendment right to free speech, that they do not serve the legitimate regulatory objective to protect patient health, and they do not meet the highest standard of scrutiny afforded such speech.xvii Most recently, the U.S. District Court for the Southern District of New York held in Amarin that "[w]here the speech at issue consists of truthful and non misleading speech promoting the off-label use of an FDA-approved drug, such speech [...] cannot be the act upon which an action for misbranding is based".xviii The Amarin court specifically held that truthful and non-misleading speech cannot be used as "evidence of intent" for the purposes of an FDCA misbranding violation.xix These trends in First Amendment jurisprudence have spurred the legislative, regulatory, and policy changes discussed below.

Healthcare economic information

On December 13, 2016, President Obama signed into law the 21st Century Cures Act ("Cures Act").xx Most relevant to this article, Section 3037 of the Cures Act amended Section 114 of the Food and Drug Administration Modernization Act ("FDAMA"), which was enacted in 1997 to create a safe harbor for manufacturers to proactively communicate or disseminate certain healthcare economic information ("HCEI") that met a "competent and reliable" evidence standard. However, communications were considered false or misleading unless the information "directly relate[d]" to an approved indication for the drug. Furthermore, the communication could be made only to a "formulary committee, or other similar entity" (i.e., not to product prescribers), and so limited the scope of manufacturer communications about their products. The amendments introduced by the Cures Act sought to clarify and expand the scope of permitted manufacturer communications regarding HCEI. Specifically, the Cures Act broadened the definition of HCEI to include:

"Any analysis (including the clinical data, inputs, clinical or other assumptions, methods, results, and other components underlying or comprising the analysis) that identifies, measures, or describes the economic consequences, which may be based on the separate or aggregated clinical consequences of the represented health outcomes, of the use of a drug."

Additionally, Section 3037 expands the scope of the audience to whom a manufacturer may communicate HCEI, so that a manufacturer may now communicate HCEI to "payors" and to formulary committee or other similar entities with knowledge and expertise of healthcare economics. Furthermore, section 3037 clarifies that HCEI must only "relate" to an FDA-approved indication of a drug, rather than be "directly" related to an approved indication. This change permits manufacturers to communicate HCEI regarding off-label uses of their products, thereby greatly expanding the scope of permitted communications.

Stakeholder Input and Draft FDA Guidance Documents

Over the years, FDA has indicated that it would revise its policies on manufacturer communications. For example, in 2011, FDA opened a docket requesting comments on scientific exchange regarding both FDA-approved and investigational products.xxi Similarly, in 2014, in a federal register notice regarding a Draft Guidance for Industry on Distributing Scientific and Medical Publications on Risk Information for Approved Prescription Drug and Biological Products, FDA stated that it "plans to issue, by the end of the calendar year, additional guidance that addresses manufacturer responses to unsolicited requests, distributing scientific and medical information on unapproved new uses, manufacturer discussions regarding scientific information more generally, and distribution of health care economic information to formulary committees and similar entities".xxii Although many years went by without modifications to FDA regulations or guidance regarding manufacturer communications, the final days of the Obama Administration did see proposed changes to FDA guidance.

In November 2016, FDA held a public hearing to solicit comment from stakeholders – including industry trade groups – on its approach to regulating manufacturer communications on off-label uses.xxiii In addition, FDA opened a formal docket to receive written comments on such issues. Although the written comments were originally due on January 9, 2017, 10 days after the comments were due, FDA published a Memorandum on Public Health Interests and First Amendment Considerations Related to Manufacturer Communications Regarding Unapproved Uses of Approved or Cleared Medical Products ("First Amendment Memorandum") and reopened the docket comment period.xxiv The First Amendment Memorandum describes FDA's response to the trends in First Amendment jurisprudence and sets forth the public health interests FDA wants to protect through its regulation of manufacturer communications. In response to this docket, many industry stakeholders submitted comments stating that although FDA's stated interests are valid and important, FDA could continue to protect those interests while expanding the scope of permissible manufacturer communications. Many respondents recommended that FDA amend its current regulations to better align with recent First Amendment jurisprudence to broaden the ability of manufacturers to communicate truthful and non-misleading information about off-label uses of their products.

In January 2017, FDA simultaneously published two draft guidance documents that further expand the scope of permissible manufacturer communications. FDA's Draft Guidance on Medical Product Communications That Are Consistent With the FDA-Required Labeling – Questions and Answers addresses manufacturer communications to all HCPs regarding information that is not contained in the FDA-required labelling, but that is "consistent with the FDA-required labeling".xxv Although the Draft Guidance leaves some questions open as to the evidentiary support that must be included with such communications, the Draft Guidance does provide helpful information to manufacturers about the permissible scope of the communications.

In the Draft Guidance, FDA proposes that it will exercise enforcement discretion regarding truthful and non-misleading manufacturer communications "consistent with" the FDA-required labelling if a communication meets each of three factors. First, the manufacturer communication must be consistent with the: a) indication; b) patient population; c) limitations and directions for handling/use; and d) dosing/administration contained in the FDA-required labelling. Second, the manufacturer communication should not make representations or suggestions that "increase the potential for harm to health relative to information in the FDA-required labeling". Third, the manufacturer communication must not represent or suggest conditions for use under which the product could not be safely and effectively used.xxvi

FDA's Draft Guidance on Manufacturer Communications with Payors, Formulary Committees, and Similar Entities – Questions and Answers addresses manufacturer communications with sophisticated healthcare audiences and implementing section 3037 of the Cures Act, discussed above.xxvii Generally, the Draft Guidance explains FDA's current thinking regarding the communication by manufacturers about HCEI. In the Draft Guidance, FDA defines the scope of the audience to whom a manufacturer may communicate HCEI to include "payors, formulary committees (e.g., pharmacy and therapeutic committees, drug information centers, technology assessment panels, pharmacy benefit managers, and other multidisciplinary entities that review scientific and technology assessments to make drug selection, formulary management, and/ or coverage and reimbursement decisions on a population basis for health care organizations".xxviii Importantly, the Draft Guidance clarifies that HCEI "pertains to the economic consequences related to the clinical outcomes of treating a disease (or specific aspect of a disease) or of preventing or diagnosing a disease" and offers various examples when HCEI "relates to" an approved indication.xxix

Additionally, the Draft Guidance clarifies when FDA would not consider HCEI to be false or misleading. FDCA section 502(a) states, in part, that HCEI "shall not be considered to be false or misleading [...] [if it] is based on competent and reliable scientific evidence [CARSE]".xxx The Draft Guidance provides guidance to manufacturers regarding how to meet this standard, stating that "FDA considers HCEI to be based on CARSE if the HCEI has been developed using generally-accepted scientific standards, appropriate for the information being conveyed, that yield accurate and reliable results".xxxi

Amended FDA Regulations

In the final days of the Obama Administration, on January 9, 2017, FDA published its final rule amending, in part, FDA's regulation on "intended use" ("Final Rule").xxxii The concept of "intended use" is central to FDA's regulation of drugs. If any article is "intended for use in the diagnosis cure, mitigation, treatment, or prevention of disease",xxxiii then the article is a drug and is subject to FDA approval and FDA regulation. Additionally, FDCA § 502(f)(1) states that an approved drug is misbranded unless its labelling bears "adequate directions for use". Although Congress exempted prescription drugs from this requirement, FDA regulations state that a prescription drug is exempt only if the drug's labelling contains "adequate information" for a use for which the drug "is intended".xxxiv Under current regulation, drug manufacturers may not include "information" in labelling regarding an unapproved use. Therefore, if an unapproved use is the manufacturer's "intended use". FDA considers the drug misbranded in violation of FDCA § 502(f)(1) and subject to FDA enforcement action.

In the Final Rule, FDA did not adopt the interpretation of "intended use" supported by drug manufacturers, who strongly disagree with FDA's current interpretation. In particular, industry believes that FDA's interpretation is contrary to the holding by various courts, such as the Amarin court, that truthful and non-misleading speech cannot provide evidence of a new intended use.

However, on February 7, 2017, FDA delayed the effective date of the Final Rule until March 21, 2017. Only one day later, MIWG, PhRMA, and BIO submitted a Petition to Stay and for Reconsideration of the Final Rule ("Petition").xxxv In response to the Petition, FDA published a notification, further delaying the effective date of, and seeking comments on, the Final Rule and the Petition ("Request for Comments"). As of this writing, public comments on the Request for Comments are due July 18, 2017.

CONCLUSION

Despite, or possibly because of, the recent activity in this area, there is still significant uncertainty regarding communication of off-label uses of products in both the EU and U.S., by companies and national authorities.

In the EU, it remains to be seen how the European Commission will respond to the suggestions set out in the recent Study, and what changes, if any, will be implemented. None of the proposals involve implementing the same rigorous standard for assessment as that required by Directive 2001/83/EC to place a product on the market. In the meantime, the circumstances in which off-label use is permitted, and promoted, by national authorities in the different Member States shows substantial divergence across the EU, particularly where financial considerations are included in the decision whether to prescribe products off-label.

Similarly, in the U.S., although FDA's positions may not change in the short term, recent court decisions on the First Amendment rights of manufacturers and the current Administration's policies lend weight to regulatory changes that would allow manufacturers to more broadly communicate about their products. In position papers and comments to FDA, industry trade associations, such as PhRMA, BIO, and other groups have proposed regulatory frameworks that they believe to be rational approaches to off-label promotion. Arguably, the most compelling of these proposals would permit truthful and non-misleading communication regarding off-label uses (consistent with the decision of the court in Amarin) to sophisticated audiences, as long as appropriate contextual information and disclosures were included with the communications. To implement such a framework, FDA must amend existing or add new regulatory safeguards.

Given the uncertainty, companies should keep a close eye on these developments before disseminating off-label information, and should work closely with regulatory and legal counsel to understand whether a particular communication, either by the company or by a national authority, may be challenged in the current regulatory environment.

Footnotes

i. Directive 2001/83/EC, Article 6.

ii. Case T-452/14 Laboratoires CTRS v Commission [2015], para. 79.

iii. Statement on bio-pharmaceutical industry complaint to the European Commission against a new Italian law Promoting off label use of medicines for economic reasons, 20 February 2015.

iv. Biopharmaceutical industry files complaint against French law promoting government-initiated off-label use without the involvement or consent of patients and their physicians, 1 September 2015.

v. Case C-185/10 Commission v Poland [2012], para. 38.

vi. Case C-179/16 F. Hoffmann-La Roche and Others.

vii. Conseil d'Etat, 1st–6th Chambers, 24 February 2017, No. 392459.

viii. The Conseil d'Etat referred to C-185/10 Commission v Poland and to C-535/11 Novartis Pharma GmbH v Apozyt GmbH.

ix. European Commission, Study on off-label use of medicinal products in the European Union, 27 February 2017.

x. For example, in 2014, France excluded Lucentis® from drug coverage and replaced it with Avastin®.

xi. CPME policy on off-label use of medicinal products, 8 April 2017, CPME/AD/Board/08042017/006_Final/EN.

xii. C-185/10 Commission v Poland [2012].

xiii. See 21 U.S.C. § 331(a), (b), (c), (k); 21 U.S.C. § 352.

xiv. See 21 U.S.C. § 321(m); 21 C.F.R. § 201.128; see e.g., Bradley v U.S., 264 F. 79 (5th Cir. 1920); U.S. v 46 Cartons, More or Less, Containing Fairfax Cigarettes, 113 F. Supp. 336 (D.N.J. 1953); American Health Products Co., Inc. v Hayes, 574 F. Supp. 1498 (S.D.N.Y. 1983).

xv. See 21 U.S.C. § 333.

xvi. See e.g., FDA, Draft Guidance for Industry: Distributing Scientific and Medical Publications on Unapproved New Uses – Recommended Practices 6 (Feb. 2014).

xvii. See Sorrell v IMS Health, Inc. 564 U.S. 552, 567 (2011); United States v Caronia, 703 F.3d 149, 166 (2d Cir. 2012).

xviii. Amarin Pharma, Inc. v FDA, 119 F. Supp. 3d 196, 226 (S.D.N.Y. 2015).

xix. Id. at 227–228.

xx. 21st Century Cures Act, Pub. L. No. 114-255, 130 Stat. 1105 (2016).

xxi. Communications and Activities Related to Off-Label Uses of Marketed Products and Use of Products Not Yet Legally Marketed; Request for Information and Comments, 76 Fed. Reg. 81508 (Dec. 28, 2011).

xxii. Draft Guidance for Industry on Distributing Scientific and Medical Publications on Risk Information for Approved Prescription Drugs and Biological Products – Recommended Practices; Availability, 79 Fed. Reg. 33569 (June 11, 2014).

xxiii. Notification of public hearing; request for comments, 81 Fed. Reg. 60299 (Sept. 1, 2016).

xxiv. Docket FDA-2016-N-1149, FDA, Manufacturer Communications Regarding Unapproved Uses of Approved or Cleared Medical Products (Jan. 2017).

xxv. FDA, Draft Guidance for Industry, Medical Product Communications That Are Consistent With the FDA-Required Labeling – Questions and Answers (Jan. 2017).

xxvi. Id. at Questions and Answers 3–5.

xxvii. FDA, Draft Guidance for Industry, Manufacturer Communications with Payors, Formulary Committees, and Similar Entities – Questions and Answers (Jan. 2017).

xxviii. Id. at Questions and Answers 4.

xxix. Id. at Questions and Answers 1.

xxx. 21 U.S.C. § 352(a) (FDCA § 502(a)).

xxxi. FDA, Draft Guidance for Industry, Manufacturer Communications with Payors, Formulary Committees, and Similar Entities – Questions and Answers (Jan. 2017), Questions and Answers 9.

xxxii. See 82 Fed. Reg. 2193 (Jan. 9, 2017).

xxxiii. 21 U.S.C. § 321(g); see also Pure Food and Drugs Act, ch. 3915, 34 Stat. 768, 769 (June 30, 1906).

xxxiv. 21 C.F.R. § 201.100(c)(1).

xxxv. Docket FDA-2015-N-2002, MIWG, PhRMA, and BIO, Petition to Stay and for Reconsideration (Feb. 8, 2017).

Acknowledgment

The authors would like to thank Ashley Bender, an associate at Arnold & Porter Kaye Scholer, for her assistance with this article.

Originally published by International Comparative Legal Guide to: Pharmaceutical Advertising 2017, 14th Edition, (London: Global Legal Group, Ltd.).

The content of this article is intended to provide a general guide to the subject matter. Specialist advice should be sought about your specific circumstances.

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Registration (you must scroll down to set your data preferences)

Mondaq Ltd requires you to register and provide information that personally identifies you, including your content preferences, for three primary purposes (full details of Mondaq’s use of your personal data can be found in our Privacy and Cookies Notice):

  • To allow you to personalize the Mondaq websites you are visiting to show content ("Content") relevant to your interests.
  • To enable features such as password reminder, news alerts, email a colleague, and linking from Mondaq (and its affiliate sites) to your website.
  • To produce demographic feedback for our content providers ("Contributors") who contribute Content for free for your use.

Mondaq hopes that our registered users will support us in maintaining our free to view business model by consenting to our use of your personal data as described below.

Mondaq has a "free to view" business model. Our services are paid for by Contributors in exchange for Mondaq providing them with access to information about who accesses their content. Once personal data is transferred to our Contributors they become a data controller of this personal data. They use it to measure the response that their articles are receiving, as a form of market research. They may also use it to provide Mondaq users with information about their products and services.

Details of each Contributor to which your personal data will be transferred is clearly stated within the Content that you access. For full details of how this Contributor will use your personal data, you should review the Contributor’s own Privacy Notice.

Please indicate your preference below:

Yes, I am happy to support Mondaq in maintaining its free to view business model by agreeing to allow Mondaq to share my personal data with Contributors whose Content I access
No, I do not want Mondaq to share my personal data with Contributors

Also please let us know whether you are happy to receive communications promoting products and services offered by Mondaq:

Yes, I am happy to received promotional communications from Mondaq
No, please do not send me promotional communications from Mondaq
Terms & Conditions

Mondaq.com (the Website) is owned and managed by Mondaq Ltd (Mondaq). Mondaq grants you a non-exclusive, revocable licence to access the Website and associated services, such as the Mondaq News Alerts (Services), subject to and in consideration of your compliance with the following terms and conditions of use (Terms). Your use of the Website and/or Services constitutes your agreement to the Terms. Mondaq may terminate your use of the Website and Services if you are in breach of these Terms or if Mondaq decides to terminate the licence granted hereunder for any reason whatsoever.

Use of www.mondaq.com

To Use Mondaq.com you must be: eighteen (18) years old or over; legally capable of entering into binding contracts; and not in any way prohibited by the applicable law to enter into these Terms in the jurisdiction which you are currently located.

You may use the Website as an unregistered user, however, you are required to register as a user if you wish to read the full text of the Content or to receive the Services.

You may not modify, publish, transmit, transfer or sell, reproduce, create derivative works from, distribute, perform, link, display, or in any way exploit any of the Content, in whole or in part, except as expressly permitted in these Terms or with the prior written consent of Mondaq. You may not use electronic or other means to extract details or information from the Content. Nor shall you extract information about users or Contributors in order to offer them any services or products.

In your use of the Website and/or Services you shall: comply with all applicable laws, regulations, directives and legislations which apply to your Use of the Website and/or Services in whatever country you are physically located including without limitation any and all consumer law, export control laws and regulations; provide to us true, correct and accurate information and promptly inform us in the event that any information that you have provided to us changes or becomes inaccurate; notify Mondaq immediately of any circumstances where you have reason to believe that any Intellectual Property Rights or any other rights of any third party may have been infringed; co-operate with reasonable security or other checks or requests for information made by Mondaq from time to time; and at all times be fully liable for the breach of any of these Terms by a third party using your login details to access the Website and/or Services

however, you shall not: do anything likely to impair, interfere with or damage or cause harm or distress to any persons, or the network; do anything that will infringe any Intellectual Property Rights or other rights of Mondaq or any third party; or use the Website, Services and/or Content otherwise than in accordance with these Terms; use any trade marks or service marks of Mondaq or the Contributors, or do anything which may be seen to take unfair advantage of the reputation and goodwill of Mondaq or the Contributors, or the Website, Services and/or Content.

Mondaq reserves the right, in its sole discretion, to take any action that it deems necessary and appropriate in the event it considers that there is a breach or threatened breach of the Terms.

Mondaq’s Rights and Obligations

Unless otherwise expressly set out to the contrary, nothing in these Terms shall serve to transfer from Mondaq to you, any Intellectual Property Rights owned by and/or licensed to Mondaq and all rights, title and interest in and to such Intellectual Property Rights will remain exclusively with Mondaq and/or its licensors.

Mondaq shall use its reasonable endeavours to make the Website and Services available to you at all times, but we cannot guarantee an uninterrupted and fault free service.

Mondaq reserves the right to make changes to the services and/or the Website or part thereof, from time to time, and we may add, remove, modify and/or vary any elements of features and functionalities of the Website or the services.

Mondaq also reserves the right from time to time to monitor your Use of the Website and/or services.

Disclaimer

The Content is general information only. It is not intended to constitute legal advice or seek to be the complete and comprehensive statement of the law, nor is it intended to address your specific requirements or provide advice on which reliance should be placed. Mondaq and/or its Contributors and other suppliers make no representations about the suitability of the information contained in the Content for any purpose. All Content provided "as is" without warranty of any kind. Mondaq and/or its Contributors and other suppliers hereby exclude and disclaim all representations, warranties or guarantees with regard to the Content, including all implied warranties and conditions of merchantability, fitness for a particular purpose, title and non-infringement. To the maximum extent permitted by law, Mondaq expressly excludes all representations, warranties, obligations, and liabilities arising out of or in connection with all Content. In no event shall Mondaq and/or its respective suppliers be liable for any special, indirect or consequential damages or any damages whatsoever resulting from loss of use, data or profits, whether in an action of contract, negligence or other tortious action, arising out of or in connection with the use of the Content or performance of Mondaq’s Services.

General

Mondaq may alter or amend these Terms by amending them on the Website. By continuing to Use the Services and/or the Website after such amendment, you will be deemed to have accepted any amendment to these Terms.

These Terms shall be governed by and construed in accordance with the laws of England and Wales and you irrevocably submit to the exclusive jurisdiction of the courts of England and Wales to settle any dispute which may arise out of or in connection with these Terms. If you live outside the United Kingdom, English law shall apply only to the extent that English law shall not deprive you of any legal protection accorded in accordance with the law of the place where you are habitually resident ("Local Law"). In the event English law deprives you of any legal protection which is accorded to you under Local Law, then these terms shall be governed by Local Law and any dispute or claim arising out of or in connection with these Terms shall be subject to the non-exclusive jurisdiction of the courts where you are habitually resident.

You may print and keep a copy of these Terms, which form the entire agreement between you and Mondaq and supersede any other communications or advertising in respect of the Service and/or the Website.

No delay in exercising or non-exercise by you and/or Mondaq of any of its rights under or in connection with these Terms shall operate as a waiver or release of each of your or Mondaq’s right. Rather, any such waiver or release must be specifically granted in writing signed by the party granting it.

If any part of these Terms is held unenforceable, that part shall be enforced to the maximum extent permissible so as to give effect to the intent of the parties, and the Terms shall continue in full force and effect.

Mondaq shall not incur any liability to you on account of any loss or damage resulting from any delay or failure to perform all or any part of these Terms if such delay or failure is caused, in whole or in part, by events, occurrences, or causes beyond the control of Mondaq. Such events, occurrences or causes will include, without limitation, acts of God, strikes, lockouts, server and network failure, riots, acts of war, earthquakes, fire and explosions.

By clicking Register you state you have read and agree to our Terms and Conditions