(2000; 81 pages)
WHO Guidelines for the regulatory assessment of medicinal products for use in self-medication*
* The text of the Guidelines was endorsed at a consultation on 15-16 April 1999. Participants included: Dr D. Bown, United States of America, Mr G. Kisuule, Uganda, Dr H. Ogasawara, Japan, Dr Ch. Siregar, Indonesia, Mrs G. Williams, United Kingdom, and included representatives from the International Federation of Pharmaceutical Manufacturers Associations (IFPMA) and the World Self Medication Industry (WSMI).
Self-care can be defined as a primary public health resource in the health care system. It concerns the health activities and health decisions of individuals and includes self-medication, self-treatment, social support in illness, and first aid in everyday life.
The decision to allow products to be used in self-medication through over-the-counter (OTC) sale is currently of great interest in many countries. Drug regulatory and health authorities have to consider the types of medicinal products for which marketing is appropriate, safe and rational in the interests of public health. The following guidelines have been devised by WHO for the use of regulatory authorities and other interested parties and are available from: Quality and Safety of Medicines, Essential Drugs and Medicines Policy (EDM), World Health Organization, 1211 Geneva 27, Switzerland, http://www.who.int
It has become widely accepted that self-medication has an important role to play in the health care system. Recognition of the responsibility of individuals for their own health, and awareness that professional care for minor ailments is often unnecessary have contributed to this view. Improvements in people's general knowledge, level of education and socioeconomic status in many countries form a reasonable basis for successful self-medication.
New drugs with specific pharmacological action, such as histamine H2-receptor antagonists, nonsteroidal anti-inflammatory drugs (NSAID) and nicotine preparations for cessation of smoking, have been successfully reclassified from prescription to non-prescription status in many countries. Regulatory assessment of a change from prescription to non-prescription status should be based on medical and scientific data, on safety and efficacy of the compound, and on rationality in terms of public health.
The present guidelines propose criteria and methods which drug regulatory authorities can employ in determining the suitability of medicinal products for use in self-medication. The term "assessment" is used rather than "clinical evaluation", since in many cases the process will involve a review of existing data and experience and not the performance of new clinical trials or investigations, though the latter may occasionally be necessary. The guidelines are also intended for use by marketing authorization holders applying for the classification of a prescription medicinal product to be switched to non-prescription sale. Lastly, they provide guidance on documentation to accompany applications for marketing authorization of new active substances which have not been marketed as prescription medicines but for self-medication.
The initiative for the review of prescription products or any new product that might reasonably be released for self-medication has generally been taken by the pharmaceutical industry in the form of documented proposals to national drug regulatory authorities. Occasionally, such authorities have themselves taken steps to reclassify medicinal products and make them available for self-medication. In some cases, moreover, products have been changed back from self-medication to prescription drug status because new safety issues have arisen. This underlines the fact that it is of crucial importance to carefully monitor the use of medicinal products and post-marketing data on adverse effects and respond adequately and quickly to possible harmful developments.
Scope of the guidelines
These guidelines address the criteria for regulatory assessment of safety and efficacy of self-medication products, including new active substances that have not been marketed as prescription medicines, drugs that have hitherto been available only on prescription, and those for which new information requires the re-evaluation of safety. These guidelines do not address homoeopathic medicines, in vitro diagnostic products or other medicinal preparations such as vitamin and mineral supplements, and some medicines of plant origin that are not well characterized.
Definition of medicinal products for self-medication
Medicinal products for self-medication may be defined as those not requiring a medical prescription and produced, distributed and sold primarily to consumers for use on their own initiative and responsibility when they consider such use appropriate. The term "over-the-counter (OTC) medicines" is widely used to describe this class of product. The packing, package size, labelling and product information (package insert, leaflet, directions folder or other accompanying text) will generally be designed and written to ensure appropriate self-medication.
The distinction between self-medication products and prescription medicines is not a sharp one and differences in dosage and/or in indications can lead to differences in classification. For example, ibuprofen is sold only on prescription at high dose for treatment of arthritis and over-the-counter at low doses for treatment of headaches and other minor pain. It is often the practice to provide self-medication in smaller packages.
Basic criteria for a self-medication product
A self-medication product should fulfil at least the following three criteria:
(1) Active ingredient: The active ingredient at the intended dose should have low inherent toxicity (e.g. no reproductive toxicity, genotoxic or carcinogenic properties relevant to human use, unless such hazard can be appropriately addressed by labelling).
(2) Intended use: The intended use should be appropriate for self-medication. Use of the product should not unduly delay diagnosis and treatment of a condition requiring medical attention.
(3) Product properties: The product should not have properties that make it undesirable. For example, it should not have an unfavourable adverse event profile, require a physician's supervision for monitoring during therapy, represent a significant risk of dependence or abuse, or display other limiting characteristics such as interaction with commonly used medicines or foods that may result in serious adverse reactions.
If a new chemical entity or a prescription product meets the three basic criteria, the following additional criteria may favour change of status to non-prescription sale:
(1) The use of the product has been sufficiently extensive or in high enough volume.
(2) The product has been marketed on prescription for at least five years. The time considered appropriate for a product to have been on prescription varies widely, e.g. no time specified in the European Union, three years in New Zealand, six years in Japan, and up to 10 years in the Philippines.
(3) Its adverse events give no cause for concern, and their frequency has not increased unduly during the marketing period.
The reason for requiring five years prescription marketing is that withdrawals from the market for adverse events or for major changes in product information have usually occurred during the first three to five years after marketing in those countries with effective safety monitoring systems. A high level of use permits detection of relatively rare but serious adverse effects and sometimes the detection of an increased frequency of a particular adverse event. High use is also likely to mean that the drug has been used in a broad range of people with a wide variety of concomitant diseases, concomitant drugs and risk factors for adverse events. It should be noted that the period of use may vary in countries with well-developed pharmacovigilance systems.
The criteria outlined above are based on the normal stepwise widening of exposed patients in three consecutive stages of drug development:
(1) Investigational use prior to marketing authorization with limited controlled exposure of a relatively small group of people in clinical trials who are monitored closely for adverse effects.
(2) Prescription marketing entailing exposure of potentially large numbers of people, though limited to those who go to a physician and for whom the physician considers the drug has a positive risk/benefit balance in the treatment of a disease.
(3) Marketing and commercial promotion for self-medication - involving the increasing exposure of potentially enormous numbers of people -when concomitant diseases and other medications used may vary, and other risk factors such as pregnancy, lactation, working conditions, driving, sport, alcohol use, and potential interaction with climate, sun or food may be present. It should be noted that systems to monitor adverse reactions to self-medication products may not always exist.
Only for a few drugs will information from clinical trials prior to use be enough to support general availability in self-medication form, because such trials are conducted in selected populations monitored intensively for efficacy and safety. However, experience from marketing elsewhere in the world may provide suitably detailed data on exposure under conditions of use that are sufficiently similar to the situation in a particular country. Additional clinical studies may sometimes be necessary in the target consumer population where the product is expected to be used.
Consumers may believe that a medicinal product not subject to a medical prescription is less harmful than the same product under medical prescription. Labelling directed to the consumer should clearly communicate both the benefits and the risks of using the product for self-medication.
Characteristics of self-medication
Self-medication involves the use of medicinal products by the consumer to treat self-recognized disorders or symptoms, or the intermittent or continued use of a medication prescribed by a physician for chronic or recurring diseases or symptoms. In practice, it also includes use of the medication for family members, especially where the treatment of children or the elderly is involved.
In order to use a non-prescription product safely and effectively, the consumer must accurately recognize symptoms, set therapeutic objectives, select a product, and determine both an appropriate dosage and schedule, taking into account the person's medical history, contraindications, concomitant diseases and concurrent medications and monitoring of the response to the treatment and adverse effects.
In the case of non-prescription medicinal products, all of the information required to permit safe and effective use must come from the labelling material, patient information texts, the individual's previous personal experience, various sources of information in the media, advertising, and advice given by health care professionals. Pharmacists play a key role in giving advice to consumers on the proper and safe use of medicinal products intended for self-medication. It is important that this role is included in training and practice.
The rapid development of new technology, the Internet, and related communication systems has opened up new possibilities for seeking information and offers important new channels for the dissemination of knowledge on medicinal product characteristics and proper use in self-medication. It should be emphasized, however, that there are marked differences in opportunities to obtain access to this information between people with different socioeconomic and educational backgrounds and in different countries. Well-tested labelling designed for a particular cultural environment can help to reduce these differences. However, it should not be used in a way that would limit the availability of the OTC product.
The benefit of self-medication is that it is voluntarily chosen by consumers for conditions when it is preferable to them. It will usually be selected for use in symptoms and conditions which the user regards as sufficiently troublesome to need medicinal treatment but not to justify consulting a physician. If the condition fails to respond, persists or becomes more severe, professional medical help should be sought. Accordingly, good self-medication should offer the individual consumer:
• Efficacy, whereby the product does what it is claimed to do;
• Reliability and safety: the individual will often choose a product which experience has shown to be suitable. The scope and duration of self-medication can be kept within safe limits by appropriate selection of approved indications, labelling texts, dosage strengths and forms, and package sizes;
• Product safety when used as recommended by the instructions;
• Acceptable risk, even when used for a longer duration, at a higher dose, or somewhat differently than recommended in the instructions;
• Wider availability of medicines;
• Greater choice of treatment;
• Direct, rapid access to treatment;
• An active role in his or her own health care;
• Self-reliance in preventing or relieving minor symptoms or conditions;
• Educational opportunities on specific health issues (i.e. stop-smoking aids and products to treat heartburn);
• Economy, particularly since medical consultations will be reduced or avoided.
At the community level, good self-medication can also provide benefits such as saving scarce medical resources from being wasted on minor conditions, lowering the costs of community-funded health care programmes (including prescription reimbursement systems), and reducing absenteeism from work due to minor symptoms.
Self-medication has a number of potential risks. In particular, the ordinary user will usually have no specialized knowledge of the principles of pharmacology or therapy, or of the specific characteristics of the medicinal product used. This results in certain potential risks for the individual consumer:
• Incorrect self-diagnosis;
• Failure to seek appropriate medical advice promptly;
• Incorrect choice of therapy;
• Failure to recognize special pharmacological risks;
• Rare but severe adverse effects;
• Failure to recognize or self-diagnose contraindications, interactions, warnings and precautions;
• Failure to recognize that the same active substance is already being taken under a different name (products with different trademarks may have the same active ingredient);
• Failure to report current self-medication to the prescribing physician (risk of double medication or harmful interaction);
• Failure to recognize or report adverse drug reactions;
• Incorrect route or manner of administration;
• Inadequate or excessive dosage;
• Excessively prolonged use;
• Risk of dependence and abuse;
• Risks at work or in sport;
• Food and drug interactions;
• Storage in incorrect conditions or beyond the recommended shelf-life.
At the community level, improper self-medication could result in an increase in drug-induced disease and in wasteful public expenditure.
It is important to realize that many of these risks are not unique to self-medication: they can also occur in prescription-only medication, particularly if the patient consults several physicians for the illness or lacks counselling during therapy.
In selecting the types of medicinal products that can be used for self-medication, the aim should be to exploit the benefits listed above and to minimize the risks.
Acceptable degrees of risk
Safeguards need to be provided to make self-medication as safe and effective as possible. Self-medication is a valid part of health care provided that the medicinal products used have been shown to be safe and effective for their intended purpose, are sold with explicit directions for their use, and are manufactured to high quality according to the principles of good manufacturing practice (GMP). Safeguards relate largely to the selection of the most suitable and safe substances, doses and dosage forms and may involve the provision of special information or public education, the control of advertising and package texts, or the limitation of distribution channels.
In accepting the principle of self-medication, the community makes a positive judgement on the risk/benefit ratio of self-medication as a whole. It cannot reasonably be assumed that benefit will always be assured or the risk will be entirely eliminated. Since the risk factors listed above vary in degree from one individual to another and one situation to another, there may be patients who will suffer inconvenience or harm. However, if the degree and incidence of such harm are not disproportionate to the benefits offered, the risk will be acceptable.
Only long-term exposure of the population can uncover rare or delayed adverse events. Consequently, there continues to be a need to revise product information, or even to withdraw medicinal products aimed at self-medication when necessary.
Adaptation to the community
Any assessment of suitability of a medicinal product for use in self-medication should take into account the situation and population in which it is proposed. Clearly, in a region where endemic disease occurs in large areas without adequate medical services, the potential benefit of certain medicinal products may outweigh risks that would not be acceptable elsewhere; policies also need to reflect the degree of literacy and general education of the population concerned.
General basis for regulatory assessment
Basic criteria for a self-medication product are set out above and include the following.
The pharmacokinetics, pharmacodynamics, indications, safety and efficacy, and toxic or allergenic potential of a medicinal product should have been reasonably well established and documented in humans before its eligibility for use in self-medication can be assessed.
Where a new active pharmaceutical substance that has not been marketed as a prescription medicine is being considered for use in self-medication, the previous studies will have been conducted largely in animals. The clinical trials and investigations with such a substance should reflect the self-medication situation, and subsequent collections of post-marketing data on long-term safety and efficacy may be necessary. These data must be sufficient to meet the criteria for self-medication.
When the release for self-medication of a medicinal product hitherto used only on prescription is being considered, it should first have been properly investigated and then employed for a number of years on a considerable scale in prescription medicine. The older the original product, however, the more likely it is that the original studies will prove to fall short of present-day investigational standards, and the more necessary it will be to rely on subsequent evidence from incidental studies, adverse reaction reporting and general experience in the field.
Similarly, where the future status is being considered of a product already in use for a long time for self-medication, there is commonly a lack of formal prospective clinical studies matching present-day standards. Again it will often be necessary to draw conclusions from practical and circumstantial data, but if the medicinal product has been used on a large scale this may be possible.
Where the suitability of a fixed-combination product for use in self-medication is being considered, the basic principle will apply that the combination should be therapeutically rational, including only ingredients necessary for the treatment and containing no active ingredients that are superfluous to the treatment of the conditions in which efficacy for self-medication is to be claimed.
Approaches to regulatory assessment and supervision
In the assessment of a medicinal product's suitability for use in self-medication, the following complementary aspects need to be considered:
(1) The active substance and the rationality of its indications;
(2) One or more specific routes of administration, dosage forms and formulations;
(3) Other specific safeguards;
(4) Suitability for self-medication status; and
(5) Labelling and package inserts and other information forming a basis for advertising and promotion.
Other aspects may require more specific additional consideration in the light of the pharmacological properties of the medicinal product, the intended indication, type of use, adverse effects or other characteristics, such as those relating to social and environmental circumstances.
Consideration of the active substance and its indications
This will involve deciding whether the active compound itself is suitable and rational for self-medication. It should include the following aspects:
• The purpose for which the product is indicated, i.e. whether this can be regarded as appropriate for self-diagnosis, self-medication and self-monitoring. Generally, such indications are for widely experienced symptoms or disorders that are readily recognizable by ordinary consumers, or that are initially diagnosed by a doctor and are often self-limiting in nature;
• Provision of reliable and consistent relief of symptoms;
• Favourable risk/benefit ratio of the product; if the indications are minor, as they generally will be in self-medication, the benefit will be quickly outweighed by potential adverse effects that are other than minor;
• The general toxicity, reproduction toxicity, genotoxicity and carcinogenicity of the compound with regard to its use in self-medication. In general, the drug must have a wide margin of safety, even if used incorrectly;
• Its potential risks in comparison with prescription drugs that are commonly used in the same patient group;
• Its mode of action and pharmacokinetics. In particular, the absorption, metabolism and excretion of the compound should not be affected by other commonly used drugs or display marked fluctuations between individuals because of concomitant diseases, interactions with food, or genetic or environmental factors (working conditions, climate, and so forth);
• Low and well-documented risks in specific patient groups, for example in elderly people, during pregnancy and lactation, and in patients with impaired liver or kidney function;
• The potential impact of widespread use on the levels of microbial resistance to antimicrobial medicines in the general population;
• Low risk of masking symptoms of underlying serious disease, resulting in delays in proper diagnosis and treatment;
• Acceptable level of risk from inappropriate use;
• Low or well-characterized incidence of adverse effects or side-effects, and contraindications for which advice or counselling is easily available;
• Drug dependence and abuse potential of the drug;
• The existence of other dosage forms of the same active ingredient that have already been approved for OTC sale.
Specific routes of administration, dosage forms and formulations
Since no active therapeutic substance is likely to be ideal in every way, it will be necessary to consider which specific presentations or formulations might be best suited to self-medication, since these can affect the medicinal product's safety, efficacy and suitability. For example, only preparations that can be administered in a manner not requiring technical expertise, assistance or patient training can be considered suitable for self-medication. Thus, oral or topical preparations will generally be suitable, but injections will usually not. It may be desirable to avoid certain types of excipient, where they are known to affect certain patient groups adversely.
Consideration of other specific safeguards
The suitability of a substance for use in self-medication can be further affected by the feasibility of providing other specific safeguards related to:
(1) Dosage: Restricting the maximum single dose or maximum daily dose may protect against danger when the medicinal product is used either correctly or incorrectly. However, it is necessary to confirm that the dose retains the necessary efficacy.
(2) Dosage strength: For children, specific dosage strengths suitable for paediatric use are preferable. For the adult population, consideration should be given to the need for several strengths, bearing in mind different uses and characteristics, though this should be balanced against any problem that may be encountered in selecting the proper dose.
(3) Dosage schedule: The recommended duration of treatment should prevent unnecessarily prolonged use. If the symptoms fail to respond adequately or persist, medical attention/consultation is necessary.
(4) Package size: The package size should be limited to a reasonable number of doses in relation to the recommended duration of the treatment. This is necessary to safeguard against misuse, particularly overdose or undue delay in seeking medical attention. There may occasionally be a need for larger packages as an option in specific, designated situations or for prolonged use.
(5) Packing material and form: Medicinal products should have a container which as far as possible prevents children gaining access to the medicine if they get hold of the container.
Suitability for self-medication status
The potential risk/benefit characteristics of the medicinal product in self-medication should be set against its risk/benefit characteristics as a prescription product since it cannot be assumed that prescription status necessarily provides a greater guarantee of safety than non-prescription status. Where prescription status has been considered preferable because a physician can perform certain diagnostic or sensitivity tests before selecting the product, ensure good patient compliance, or take steps to avoid adverse effects or interactions, it is important to know whether physicians can and do perform these tasks. If they do not, the self-medication form with appropriate warning instructions may provide a measure of safety for the user.
Similarly, in some countries a large number of medicinal products originally intended for use under medical supervision are in fact widely sold without prescription. In such instances, recognition of the real self-medication situation and the introduction of appropriate safeguards may be more in the public health interest than maintenance of a theoretical prescription status. The possibility of considering the reclassification of products to non-prescription status on the basis of experience in other countries should be considered.
Labelling and package inserts
Adequate information on appropriate use should always accompany the product. Further guidance on self-medication can be provided by health care professionals. Accompanying texts (information, advice and warnings) should be sufficiently clear and complete to enable the consumer to use the product safely, effectively and in a rational way.
When package inserts or leaflets are required by governments, they should reflect only the information that has been approved by the country's drug regulatory authority. If package inserts or leaflets are used for promotional purposes, they should comply with the WHO Ethical Criteria for Medicinal Drug Promotion (1).
In addition to approved package inserts and leaflets, the preparation and distribution of booklets and other informational material for patients and consumers should be encouraged. If such material is promotional, it should also comply with the WHO Ethical Criteria for Medicinal Drug Promotion (1).
Information for the consumer should be easily understandable and in accordance with national legislation. For self-medication products it is particularly important that the written text is easily understandable. In general, sufficient information should appear on the outer packaging to allow consumers to make a decision about suitability of the product before purchase. This is of particular importance where advice from health care professionals is not readily accessible.
The following aspects of labelling and package inserts should be considered:
• Consumer information which is simple and not confusing;
• Indication of the item as a medicinal product;
• Composition of the product including international nonproprietary name (INN)/generic name of the active substance;
• Uses for which the product is intended;
• Mode of use, including route of administration (systemic or local), maximum single dose, maximum daily dose and duration of treatment;
• Who the product is intended for (children or adults);
• Presentation of the most important precautions, contraindications and adverse effects clearly stated in easily understandable language;
• Specific warnings and information for use during pregnancy, lactation, by the elderly, or in patients with renal or hepatic failure;
• When medical advice should be sought;
• Duration of use;
• Information on storage conditions and shelf-life;
• Other measures the patient should take to control symptoms;
• Inactive ingredients listed;
• Expected benefit when the drug is used properly;
• The use of pictograms.
Advertising and promotion
Approval of product information relating to a medicine is an important part of product assessment. Advertising and promotion should always be consistent with this approved information. However, compliance of advertising with product information can only be judged after product approval. Advertising should comply with the WHO Ethical Criteria for Medicinal Drug Promotion (1).
Collection and regulatory assessment of evidence
When drug regulatory authorities assess applications for marketing authorization, three types of situation need to be distinguished:
(1) Assessment of new active substances, not marketed as prescription medicines and designed specifically for use in self-medication.
(2) Assessment for self-medication of medicinal products hitherto available only on prescription.
(3) Assessment of existing self-medication products that have not previously been evaluated.
New active substances for use in self-medication
Data for submission to the regulatory authority for review should comprise pharmaceutical, pharmacological (preclinical and general pharmacological characterization of the compound), toxicological, clinical pharmacological (clinical trials) and long-term therapeutic data (efficacy and safety) obtained through appropriate experimental studies in animals and humans. Clinical studies must address the specific issue of use in a representative self-medication population. Sufficient clinical experience of a new active substance must be gained before marketing authorization can be granted.
Self-medication products previously available on prescription-only
Evidence for or against the proposed use of a self-medication product previously available on prescription only may be obtained from many sources worldwide and may not be analysed in the same depth as the innovative prescription-only pharmaceutical product. Selected evidence should comprise:
(1) The original regulatory data
This will be relevant only if the product is in all respects identical to the original product. Human data will weigh much more heavily than animal data. If any of the original animal investigations suggested severe risks (e.g. carcinogenicity), the risks should be reassessed in the light of subsequent experience in humans.
(2) Clinical data obtained post-marketing
Trials performed according to the latest standards and relating closely to proposed use in self-medication should be accorded the greatest weight.
(3) Data on drug utilization and consumption
These can be helpful in determining the way in which the product has been employed by physicians (volume of use, major indications in practice, precautions normally taken), and particularly in interpreting alleged risks.
(4) Reported adverse reactions or interactions
The profile, frequency and severity of adverse events, reactions or drug interactions should be examined. Situations in which the evidence is critically assessed such as well-controlled clinical or epidemlological studies, are preferable to unevaluated observations of adverse reactions. Data from sources that have collected adverse drug reaction data from different countries for long periods of time may be useful, in particular, information from the WHO International Drug Monitoring Programme (2).
(5) Current scientific data
The pharmaceutical form and packaging should be considered; any available clinical studies, field data and market-related studies on consumer use of the product for self-medication should be examined.
Self-medication products not previously evaluated
In reassessing the status of an existing self-medication product, the following steps should be considered:
(1) Review of justification for the product (single active ingredient or combination), its efficacy, adverse effects, patterns of use, and labelling, particularly for consumer use.
(2) Assessment of the risk/benefit of the product.
(3) Action to be taken to deal with emerging problems. When steps have been taken (e.g. publication of warnings or imposition of limitations on package size or distribution) the effect of these measures should be assessed.
Assessment of new strengths, formulations, doses, indications or combinations
Careful assessment is also necessary when it is proposed to make the medicinal product available without prescription in a new strength, in a new formulation, at a new dose, using a new route of administration, for a new age group or for a new indication, particularly if the indication has not previously been approved without a medical prescription. In addition to an assessment of the rationality of such a proposal, the safety and risk/benefit of a medicinal product in the new circumstances should be evaluated.
A medicinal product containing a new combination of two or more active substances, which are available in two separate products, neither of which is subject to a medical prescription, will not automatically be classified as a non-prescription product. The applicant needs to demonstrate that the combination offers an advantage over the separate active substances, and that the risk is acceptable.
1. Ethical Criteria for Medicinal Drug Promotion. World Health Organization, Geneva, 1988. ISBN 92 4 154239 X.