2. European Legislation – Directive 2001/83

1. European Legislation – Directive 2001/83

(This section is organised in the form of a book, please follow the blue arrows to navigate through the book or by following the navigation panel on the right side of the page.)

The overarching legislation regulating promotion of medicinal products in Europe is Directive 2001/83/EC, and therein in Articles 86 to 100 under ‘Title VIII, Advertising’ and Title VIIIa ‘Information and Advertising’. Due to the fact that the EU legislation is a directive and member states must incorporate its provisions into their national law, but are free in the legal formulation, there are significant differences between national jurisdictions (However, national authorities must ensure provisions are correctly applied and inform the Commission accordingly by a deadline) [1] . In some cases, regulatory authorities offer detailed guidance at a national level. [2]

For example, in France, advertisement for medicinal products to both, the general public or health professionals must be pre-approved by the ANSM (The National Agency for the Safety of Medicines and Health Products (L'Agence nationale de sécurité du médicament et des produits de santé)) (Public Health Code (PHC) Articles L.5122-8, 9, R.5122-5 to 7, 12 to 16). The approval document by the ANSM is called an advertisement “visa”. In contrast, advertising for medicinal products in Germany needs no approval in general or specifically. There is also no obligation in Germany to provide competent authorities with advertising material.

1.1. Definition with inclusions - exemptions

Article 86

1) defines advertising for Title VIII as:
‘any form of door-to-door information, canvassing activity or inducement designed to promote the prescription, supply, sale or consumption of medicinal products’; it includes in particular the following topics:

• advertising of medicinal products to the general public
• advertising of medicinal products to persons qualified to prescribe or supply them,
• visits by medical sales representatives to persons qualified to prescribe medicinal products,
• the supply of samples,
• the provision of inducements to prescribe or supply medicinal products, by the gift, offer or promise of any benefit or bonus, whether in money or in kind, except when their intrinsic value is minimal,
• sponsorship of promotional meetings attended by persons qualified to prescribe or supply medicinal products,
• sponsorship of scientific congresses attended by persons qualified to prescribe or supply medicinal products and in particular payment of their travelling and accommodation expenses in connection therewith.

2) The following are not covered by this Title:

• the labelling and the accompanying package leaflets,
• correspondence, possibly accompanied by material of a non-promotional nature, needed to answer a specific question about a particular medicinal product,
• factual, informative announcements and reference material relating, for example, to pack changes, adverse-reaction warnings as part of general drug precautions, trade catalogues and price lists, provided they include no product claims,
• information relating to human health or diseases, provided that there is no reference, even indirect, to medicinal products.

[Information can be categorised as ‘promotional’ or ‘non-promotional’. From paragraph 2 of article 86 it can be inferred that those certain items are specifically exempt from the rules set by the directive, but only if they are non-promotional in nature. ‘Promotional information’ includes advertising and sales materials and/or activities related to specific products. ‘Non-promotional’ information in the directive covers legally mandated information (in the directive PL and labelling; but also consider what is mentioned in lesson 1 in this course, e.g., EPARs), and other items, which are, however, defined by restrictive wording such as ‘non-promotional nature’, ‘no product claims’ ‘no reference, even indirect, to medicinal products’ thus distinguishing them from ‘promotional’. Regulatory Authorities are observant of press releases and/or other material to ensure that they are not promotional. Regulators are also vigilant of any methods that may be used to promote medicinal products indirectly.Moreover, it is common practise for pharmaceutical companies within their framework of self-regulation to monitor the ‘scene’ and take action when violations . (see also 2.4 measures to monitor).]

Article 87

States that:

1)  a medicinal product without a marketing authorisation cannot be advertised; all parts of an advertisement must comply with the particulars listed in the summary of product characteristics (SmPC)

2)  advertising shall encourage the rational use of the medicinal product, by presenting it objectively and without exaggerating its properties and shall not be misleading

1.2. Advertising to the general public

Article 88

1)  Member states shall prohibit advertising to the general public of medicinal products:

• available on prescription only,
• containing psychotropic or narcotic substances.

2)  medicinal products may be advertised to the public when they are intended for use without the intervention of a medical practitioner (non-prescription medicinal products or over-the-counter (OTC)).

3)  Member states may ban the advertising of products that are reimbursed.

4)  Vaccination campaigns are an exception, when approved by competent authorities. [An exception for vaccine products is grounded in the fact that member states encourage individuals to get vaccinated in the interest of collective public health.]

5)  Member states shall ban Television advertising for medicinal products and medical treatment available only on prescription (accd. to Article 14 of Directive 89/552/EEC).

6)  Member states shall prohibit direct distribution of medicinal products to the public by the industry for promotional purposes.

Article 89

1)  The advertisement to the general public should:

a)  make clear that the message is an advertisement, and that it concerns a specific medicinal product.

b)  contain at a minimum the following information:

• the name (and generic name of the active substance) of the product,
• the information for correct use, and
• an express and legible invitation to carefully read the instructions on the package leaflet and/or on the outer packaging.

2)  If used solely as a reminder Member States may decide that the advertising of a medicinal product to the general public, includes only the name of the product or its international non-proprietary name, or the trademark.

Article 90

Advertising shall not contain any material with misleading messages by:

• giving the impression that a medical consultation or surgical operation is unnecessary;

• suggesting that the effects of taking the medicine are guaranteed, are unaccompanied by adverse reactions or are better than, or equivalent to, those of another treatment or medicine;

• suggesting that the health of the subject can be enhanced by taking the medicine;

• suggesting that the health of the subject could be affected by not taking the medicine (except in relation to authorised vaccination campaigns);

• exclusively or principally addressing children;

• referring to a recommendation by scientists, health professionals or celebrities;

• suggesting that the medicinal product is a foodstuff, cosmetic or other consumer product;

• suggesting that the safety or efficacy of the medicinal product is due to the fact that it is natural;

• presenting case histories that could lead to erroneous self-diagnosis and refrain from using improper, alarming or misleading terms or pictorial representations to make recovery claims or disease representations

To note:

Direct-to-Consumer advertising (DTCA)[1] of prescription medicines refers to the marketing and advertising of pharmaceutical products directly to consumers as patients, as opposed to specifically targeting health professionals. It is only completely legal in New Zealand and the United States, but subject to regulations regarding the balanced disclosure of a prescription's benefits in comparison to its risks. [2]

1.3. Advertising to Prescribers and Suppliers (Healthcare professionals)

Article 91

Advertising of any medicinal product is allowed to persons qualified to prescribe or supply products
(1)  if essential information compatible with the SmPC is provided and prescription classification (supply classification) is stated.

Member states may also require Information of the price and conditions for reimbursement.

Article 92
This article concerns any documentation on a medicinal product which is part of the promotion of that product.

1. Documentation shall include, as a minimum, the particulars listed in Article 91(1) and shall state the date of authoring or last revision.

2. All the information shall be accurate, up-to-date, verifiable and complete.

3. Quotations as well as tables and other illustrations taken from medical journals or other scientific works shall be faithfully reproduced and the precise sources indicated.

Interactions between health practitioners and medicinal product providers are governed by Articles 93 to 96.

Article 93  

Medical sales representatives shall be given adequate training and have sufficient scientific knowledge for providing information which is precise and as complete as possible about the medicinal products. This includes the SmPC and, where allowed in a Member State, details of the price and conditions for reimbursement. They shall duly report any information about the use of the medicinal products, particularly any adverse reactions reported to them by the persons they visit.

Article 94

1)  no gifts, pecuniary advantages or benefits in-kind [e.g. services] should be supplied, offered or promised to persons qualified to prescribe and supply medicinal products, unless they are inexpensive and relevant to the practice of medicine or pharmacy’.

2)  hospitality at sales promotion meetings should be reasonable and never extended to anyone other than healthcare professionals.

Article 95

The provisions of Article 94(1) shall not prevent hospitality being offered, directly or indirectly, at events for purely professional and scientific purposes; such hospitality shall always be strictly limited to the main scientific objective of the event; it must not be extended to persons other than health-care professionals.

Article 96

The supply of free samples is strictly for health care professionals, only on an exceptional basis, in limited amounts, in response to a written request and identical to the smallest presentation of the product on the market. Each sample shall be marked ‘free medical sample — not for sale’   or shall show some other wording having the same meaning.

1.4. Effective measures to monitor

Article 97

This article details the measures that member states should take in order to effectively control the advertising in their jurisdiction.  Member states shall ensure that adequate and effective methods to monitor advertising and to prohibit the diffusion of misleading advertising exist. 

This should include legal provisions under which persons or organisations may take legal action against any advertisement inconsistent with this Title (meaning Title VIII), or bring such advertisement before an administrative authority competent either to decide on complaints or to initiate appropriate legal proceedings.

However, none of the measures shall exclude the voluntary control of advertising of medicinal products by self-regulatory bodies and recourse to such bodies, if proceedings before such bodies are possible in addition to the judicial or administrative proceedings referred to.

Article 98
This addresses the marketing authorisation holder, who:

• shall establish, a scientific service in charge of information about the medicinal products which he places on the market.

• keep available for, or communicate to, the respective authorities, a sample of all advertisements together with a statement indicating the persons to whom it is addressed, the method of and the date of first dissemination,

• ensure that advertising of medicinal products conforms to the requirements of this Title,

• verify that medical sales representatives have been adequately trained and fulfil the obligations imposed upon them by Article 93,

• ensure that the decisions taken by the authorities are immediately and fully complied with.

In addition, this article states that Member States shall not prohibit the promotion of a medicinal product by the holder of the marketing authorisation and one or more companies nominated by him, also called ‘co-promotion’.

Article 99
The main provision here is that Member States shall determine in particular what penalties shall be imposed should national provisions (based on the directive) be infringed.

Sanctions for breach of national legal provisions on advertising vary from removal of misleading advertisement, publication of corrective statements, to fines or imprisonment of responsible individuals under a criminal law framework, to administrative fines in certain jurisdictions. Sanctions may escalate if the breach of the advertising provisions is linked to an illegal inducement of a healthcare professional (HCP) and the matter falls within the remit of the national anti-bribery law or there has been a breach of the antitrust rules.

Under the self-regulatory systems, sanctions for breach of national self-regulatory codes include fines, publication of cases, issuance of corrective notices to HCPs, audits and ultimately suspension or cancellation of the company’s membership to the relevant national industry association and potentially of corresponding European industry associations, such as the EFPIA.

[Considering Articles 97 and 99, an approach that can best be described as “delegated” self-regulation is deployed in several instances. As such, it can be considered an example of a co-regulatory scheme involving industry and national medicines regulatory authorities:

To ensure that medicines promotion complies with EU and national law, governments in a number of European Union (EU) countries ‘’delegate’’ some of their responsibilities regarding the control of promotional activities to pharmaceutical industry associations under the industry’s self-regulation system and its codes of practice. Such an arrangement differs from the US —and some European countries, e.g., France—where the respective regulatory authorities (the Food and Drug Administration (FDA) [1] [2] in the US and The National Agency for the Safety of Medicines and Health Products (ANSM) in France [3] ) directly govern promotion.

The following Table (Table 1) gives a brief, abbreviated description of the self-regulation system in two select EU countries, including examples of violations ruled in breach of code for a serious offence (Table 2), adapted from a publication by Zetterqvist et al. (2015)[4] .

Table 1: Constitution and procedures (abbreviated) of self-regulation in the UK and Sweden

Table 2: Three examples of violations ruled in breach of code for a serious offence by self-regulation systems in the UK and Sweden

To complement these examples of the delegated self-regulation system, two examples from the US are shown in the following:

From the FORBES list of “Ten Misleading Drug Ads 2010” [5]

Depakote ER 

In January 2009 the FDA admonished Abbott Laboratories for distributing pharmacy flashcards that promoted Depakote ER for bipolar disorder without prominently discussing its numerous side effects. The drug's risks include potentially fatal liver damage, pancreatitis and brain and spinal cord birth defects. The flashcard also implied that Depakote ER can be used to treat mania not associated with bipolar disorder; it hasn't been approved for such use.

Eisai's Dacogen is used to treat certain rare blood cell disorders and blood cancers. In a patient brochure distributed by salespeople to doctors and nurses, Eisai claimed 38% of study patients had a positive response to the drug. This is false, the FDA said in a November 2009 warning letter. In fact, that figure was taken from a small subgroup of patients who responded well to the drug. Including all the patients in the study, the response rate was a mere 20%.

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[1] FDA: Prescription Drug Advertising | Questions and Answers
https://www.fda.gov/drugs/prescription-drug-advertising/prescription-drug-advertising-questions-and-answers#top

[2] FDA: Advertising and Promotion Guidances
https://www.fda.gov/animal-veterinary/guidance-industry/advertising-and-promotion-guidances

[3] Code de la santé publique (French Public Health Code (FPHC)), Article L5122-8

[4] Zetterqvist AV, Merlo J, Mulinari S (2015) Complaints, Complainants, and Rulings Regarding Drug Promotion in the United Kingdom and Sweden 2004–2012: A Quantitative and Qualitative Study of Pharmaceutical Industry Self-Regulation. PLoS Med 12(2): e1001785. doi:10.1371/journal.pmed.1001785
https://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC4331559&blobtype=pdf [5]https://www.forbes.com/2010/02/02/drug-advertising-lipitor-lifestyle-health-pharmaceuticals-safety_slide.html

1.5. Pre-marketing and scientific information

The European regulation makes clear that any advertising of a medicinal product is prohibited until it has been granted a marketing authorisation. Only approved medicinal products can be advertised in accordance to the terms of its marketing authorisation (no off-label use may be advertised). However, the exchange of medical and scientific information during the development of a medicine is not prohibited unless it constitutes promotion. Only technical and purely scientific information can be presented. Therefore, scientific information material, such as copies of reports on the outcome of clinical studies, or scientific presentations and publications, may be made available at scientific meetings or conferences by using the non-proprietary name of the active ingredient(s) (INN) as long as the anticipated new product name is not mentioned or otherwise identified.