Regulation of head lice products in the EU

Introduction

EU regulations specify that treatments for human diseases be classified either as a medicinal product or a medical device. Pediculosis treatments fall into both categories, as will be explored in further detail below.

In brief, there are three different classes of pediculosis treatments:

Firstly, those that act via pharmacologically active ingredients (such as insecticides like pyrethrum extract, organophosphates or carbamates). These are classified as medicinal products. Such treatments have to overcome possibilities of resistance and toxicity (for example, the phasing out of of lindane in Europe over toxological and environmental concerns).

A second more recent class of treatments are those that act via a physical mechanism, as opposed to a chemical one. These are classified as medical devices and include silicone oil-based treatments such as dimeticones. By contrast to the former class of treatments, these are non-toxic to humans and are not likely to suffer from problems of resistance.

The third class of treatments are those which are based on essential oils and herbal extracts. Efficacy claims for such treatments have been advanced under both chemical and physical headings: they are mostly registered as medical devices.

Finally, the legal classification of a head lice treatment modality does not guarantee either its safety or its efficacy, and should be supported by independently-regulated in vitro trials to determine lice mortality. National treatment recommendations should be based upon the latest randomised clinical trial data available and should be updated as new products and information become available.

A medical product is governed under EU law by the Medicinal Product Directive (MPD 2001/83/EC (1)). A medical device is governed by the Medical Device Directive (MDD 93/42/EEC (2)). This will determine the procedure to be followed to successfully license a treatment in the EU, as described below (3).

Medical devices

Definition

A medical device is defined in EU legislation as follows:

'Medical device' means any instrument, apparatus, appliance, material or other article, whether used alone or in combination, including the software necessary for its proper application intended by the manufacturer to be used for human beings for the purpose of:

• Diagnosis, prevention, monitoring, treatment or alleviation of disease;
• Diagnosis, monitoring, treatment, alleviation of or compensation for an injury or handicap;
• Investigation, replacement or modification of the anatomy or of a physiological process;
• Control of conception;
• and which does not achieve its principal intended action in or on the human body by pharmacological, immunological or metabolic means, but which may be assisted in its function by such means.

This covers any form of treatment except those with a chemical basis to their action.

Classification

Medical devices are classified according to their risk profile (Annexe IX of MDD), which depends on the degree of invasiveness, duration of application, intended use and technology of the device. These mandate higher safety requirements for devices which pose the greatest risk to health or safety. The classifications are Class I for low risk, Class II (a & b) for medium risk devices, and Class III for high-risk devices. Most pediculosis treatment devices, being non-invasive, are Class I throughout the EU, however Germany has put them in Class IIa.

Market access

The requirements for market access for a medical device are as follows:

1. It must meet the Essential Requirements for the MDD (Annex I):

• 'The devices must be designed and manufactured in such a way that, when used under the conditions and for the purposes intended, they will not compromise the clinical condition or the safety of patients, or the safety and health of users or, where applicable, other persons'
• 'The solutions adopted by the manufacturer for the design and construction of the devices must conform to safety principles, taking account of the generally acknowledged state of the art'
• 'The devices must achieve the performances intended by the manufacturer'
• '[These prior conditions] must not be adversely affected to such a degree that the clinical conditions and safety of the patients and, where applicable, of other persons are compromised during the lifetime of the device as indicated by the manufacturer, when the device is subjected to the stresses which can occur during normal conditions of use'
• 'The devices must be designed, manufactured and packed in such a way that their characteristics and performances during their intended use will not be adversely affected during transport and storage'
• 'Any undesirable side effect must constitute an acceptable risk when weighed against the performances intended'.

2. It must meet the design and construction requirements from Annex I, with the following sub-sections:

• Chemical, physical and biological properties
• Prevention of infection or microbial contamination
• Construction and environmental properties
• Certain specific requirements for devices with measuring functions
• Radiation protection
• Specific requirements for devices with an energy source (safety & supply)
• Labelling, instructions and manufacturer information
• Demonstration of conformity with these requirements using clinical data.

This last requirement has been clarified in legislation within Directive 2007/47/EC such that it is clear that each device must be supported by clinical data and evaluation, closing a loophole that had enabled some manufacturers to market products with incomplete clinical data.

3. A device must also comply with the Conformity Assessment Procedures (Article 11), also known as the Certification Procedures.

These procedures vary in their scope and requirements depending on the prior risk classification of the device. A higher risk device entails greater involvement of the regulatory body and lower self-responsibility from the manufacturer.

Class I devices are certified by the manufacturer alone. All other classifications require the participation of a Notified Body (regulatory authority appointed by the EU member states). The number of this Notified Body is affixed along with the CE marking on the device.

4. A CE marking is a mandatory marking in the EU for certain product groupings to indicate conformity with relevant EU Directives (in this case, MDD). It is affixed to the device by the legally-responsible manufacturer. A CE-marked medical device may be sold in all member states of the European Economic Area and Turkey provided the labelling and instructions are given in the relevant national language.

5. Risk management is the final component of the requirements.

The standard definition of risk is as 'the combination of the probability of occurrence of harm and the severity of that harm. (4)' From the same source, risk management for a medical device is defined as 'systematic application of management policies, procedures and practices, to the tasks of analysing, evaluating, monitoring and controlling risk'.

While absolute safety is an unobtainable goal, the relevant standards describe the recommended procedures and policies to achieve the risk management quoted above. A risk management process is a key component of medical device design. This is both a serious and an ongoing process throughout device development and device life cycle.

In summary, a medical device is one which does not achieve its purpose through physical or physic-chemical means. They are classified by risk profile. The path to market involves fulfilling Essential Requirements for safety, quality and efficacy, passing a Conformity Assessment Procedure, acquiring CE marking and having an ongoing risk management process.

Medicinal products

Definition

A medicinal product is defined as follows (Directive 2001/83/EC Art. 1 §2, amended):

• Any substance or combination of substances presented for treating or preventing disease in human beings
• Any substance or combination of substances which may be administered to human beings with a view to making a medical diagnosis or to restoring, correcting or modifying physiological functions in human beings is likewise considered a medicinal product. (1)

If there is doubt over whether a treatment is a medical device or a medicinal product, the provision of the Medicinal Product Directive are applicable.

Market Access

Any medicinal product may only be placed on the market within the European Economic Area (EEA) once a Marketing Authorisation (MA) has been granted. The key criterion within this is the risk-benefit ratio. If it can be shown through required documentation on efficacy, quality and safety that the therapeutic efficacy is greater than the potential risks, an MA will be granted. Should this risk-benefit ratio later become negative once an MA has been assigned, the product must be withdrawn from sale.

Marketing authorisation procedures

There are three different kinds of procedure to be followed for MA assignment, with different outcomes. These are the Centralised Procedure, granting MA within the whole EC; the National Procedure, granting MA within just one EEA-member state, and the Mutual-recognition/Decentralised Procedure, which grants MA to several member states.

These different procedures have similar documentation requirements in their application processes, including, but not limited to, the following:

• Manufacturer name and address
• Qualitative and quantitative particulars of all the constituents of the medicinal product
• Description of the manufacturing method
• Product details: therapeutic indications, contra-indications and adverse reactions; posology, pharmaceutical form, method and route of administration and expected shelf life
• Reasons for any precautionary and safety measures to be taken for product storage, administration or disposal of waste products
• Evaluation of environmental risks
• Description of the control methods employed by the manufacturer
• Results of physico-chemical, biological or microbiological tests, toxicological and pharmacological tests, clinical trials
• Description of pharmacovigilance and risk-management procedures as applicable
• A summary of the product characteristics, one or more specimens or mock-ups of the outer packaging and the immediate packaging of the medicinal product, together with a package leaflet.

Centralised procedure

The centralised EC procedure is codified in Regulation No. 726/2004, with a single application, evaluation, prescriptions status, name and authorisation allowing direct access to the single EC market.

Some medicinal products are required to undergo the Centralised procedure, rather than either of the alternatives. These include products developed via certain biotechnological processes (such as recombinant DNA or monoclonal antibodies) as well as those products containing a new active substance for the treatment of AIDS, cancers, Alzheimer’s and related conditions, diabetes, immune dysfunctions or viruses.

An MA may be granted by the EC if the product contains a new active substance which was not authorised prior to this regulation; or if it can be shown that the product is significant innovation — whether scientific, technical or therapeutic — or that granting an MA is clearly in patient interest across the Community.

The application is evaluated scientifically within the Committee for Medicinal Products for Human Use (CMPHR) within the European Medicines Agency (EMEA). The resulting scientific opinion is used by the European Commission to draft a Decision. Once Member States have been consulted via the Standing Committee, this Decision is adopted and an MA is granted (refs).

National (independent) procedure

These procedures are limited (as of 1 January 1998) to medicinal products which are only to be authorised in one Member State, as well as to the initial phase of the Mutual Recognition Procedure (granting of an MA by a Reference Member State).

Mutual-recognition/Decentralised procedure (MRP)/(DCP)

This procedure combination must be used in the case of products seeking an MA in more than one Member State except those subject to the Centralised Procedure according to the MPD.

MRP: If a product has been granted an MA in one Member State and application submission to other States is planned, the MA holder must initiate the MRP.

DCP: If no prior MA has been granted, the applicant should use this procedure to submit a simultaneous application to all Member States where MA is intended, and select one of these to be the Reference Member State (RMS).

These two procedures are based on recognition by relevant national authorities (Concerned Member States, CMS) of a prior assessment performed by the authorities of the RMS. This assumes there are no grounds for supposing that granting an MA would pose a potential serious risk to public health. It is possible for medicinal product names and prescription status to differ according to the various national rules in force (ref).

Continuous updating

The MA must be regularly updated during the lifetime of a medicinal product in accordance with the latest scientific understanding and regulatory requirements. New information which may affect the risk-benefit ratio of the product should be given to the relevant authorities, in addition to any communication required concerning issues of pharmacovigilance.

MA validity

The initial duration of the MA is five years. The MA may be renewed at the expiry of this period provided the risk-benefit ratio is re-evaluated. This renewed MA is then indefinitely valid except where there are justified pharmacovigilance concerns assessed by a national competent body or the Commission, in which case an additional five-year period would be granted.

Clinical data

Given the requirements within the legislation for clinical data to support either a product certification or marketing authorisation, the effectiveness of new head lice treatments once on the market should not be in doubt.

However, as explained above, many older products are being sold with incomplete or missing clinical, safety or efficacy data. Even if this were not the case, product resistance is a possibility, in which case previous clinical efficacy would no longer be relevant.

Closing remarks

The material above covers the regulations surrounding bringing a pediculosis treatment to market within the EEA. Products are either categorised as medical devices and given a product certification which depends upon their risk classification, or categorised as medicinal products, and given a marketing authorisation which varies depending on the active ingredient and market scope required. In all cases, potential treatments should be supported with up to date scientific and clinical data, as well as a robust and continuous risk assessment.

Glossary

CE    mark of conformity within the EU (Fr. “conformité européenne”)
CHMP    committee for medicinal products for human use
CMS    concerned member state
DCP    decentralised procedure
EC    European commission
EEA    European economic area
EMEA    European medicines agency
EU    European union
MA    marketing authority
MDD    medical device directive, 93/42/EEC
MPD    medicinal product directive, 2001/83/EC
MRP    mutual recognition procedure
RMS    reference member state

Bibliography

1. Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use (Consolidated version: 30/12/2008).
2. Council Directive 93/42/EEC of 14 June 1993 concerning medical devices.
3. Heukelbach, Joerg. Management and Control of Head Lice Infestations. 1st ed. Bremen: UNI-MED, 2010. 978-3-8374-1203-1.
4. ISO 14971: 2007 Medical devices: Application of risk management to medical devices.