These guidelines are based upon and complement the WHO Guiding Principles for Small National Drug Regulatory Authorities (2). They are intended to assist governments in formulating laws and regulations to define and control the national market in medicinal products in the interest of public health. They describe an administrative framework for a regulatory system intended to assure the quality, safety and efficacy of licensed (authorized) medicinal products, and to authorize withdrawal of unsafe and/or illicit medicinal products from the market.
The advice is structured on the assumption that only in exceptional circumstances will a small authority become engaged in full evaluation of all toxicological, pharmacological or clinical properties of a novel medicinal product (for example, a new chemical entity) during the regulatory assessment for marketing authorization. In most instances, the decision will be guided by the regulatory status of the product in the country of origin on the basis of information such as provided through the WHO Certification Scheme on the Quality of Pharmaceutical Products moving in International Commerce (3). However, such approval may depend on a knowledge of, and acceptance of the standards and competence of the drug regulatory authority of the exporting country, by the drug regulatory authority of the importing country.
1. To establish a framework for drug regulation through the establishment of a national drug regulatory authority.
2. The primary responsibility of a drug regulatory authority is to operate a system of administration and enforcement intended to ensure that all medicinal products subject to its control conform to acceptable standards of quality, safety and efficacy; the promotion and marketing of medicinal products is in accordance with product information as approved; the use of drugs is rational; and that all personnel, premises and practices employed to manufacture, store, distribute and sell, supply and dispense these products comply with requirements to ensure the continued conformity of the products with these standards up to the time of usage/consumption.
3. These objectives can be effectively achieved only if:
(a) there is in place a mandatory system of licensing/authorizing of:
(i) all medicinal products, whether locally manufactured or imported;
(ii) all local manufacturers, importing and exporting agents, and distributors; and
(iii) all premises and facilities used locally to manufacture, store or distribute medicinal products.
(b) all stages of manufacture and distribution of medicinal products are supervised by appropriately qualified professional staff;
(c) the licensing/authorizing system is complemented by an efficient system of inspection with access to quality control laboratory facilities;
(d) the legislation is enforceable.
4. In addition to providing for licensing/authorizing, a law on medicinal products must also define the terms of reference, powers and functions of the drug regulatory authority; powers of enforcement; and include provision on the right to appeal or otherwise react to the decisions of the drug regulatory authority.
Scope and extent of the legislation2
2 This text uses the terms both “law” and “legislation”. In formulating the legal provisions, it should be noted that certain regulatory matters will be specified in the main statue (enabling or principal law, act or decree) while other matters will be addressed in subsidiary legal texts such as orders, by-laws, regulations and the like.
5. The scope of the term “medicinal product” must be defined in all encompassing terms to include, at least, pharmaceutical, biological (vaccines, blood products, other biologicals) and herbal products, including traditional medicines (not harvested by traditional medicine practitioners and sold in package form), products known in many countries as “pharmafoods”, “nutriceuticals”, or “cosmeceuticals” intended for therapeutic use and whether for animal or human use. The drug regulatory authority must also determine to what extent it intends to exempt related products, such as diagnostic materials, medical devices, cosmetics, health foods and food supplements from its scope of issuing marketing authorizations. It must also be determined in the legislation whether it includes or excludes related products. In borderline cases it might be left to the regulatory authority to decide whether a substance or preparation is considered as a medicinal product.
6. The legislation must apply to all institutions and individuals, within both the public and private sectors, that are engaged in, or connected with any aspect of manufacture, promotion, procurement, distribution, or sale or supply of medicinal products.
Terms of reference for the drug regulatory authority
7. The terms of reference, functions, responsibilities, powers and composition of the Authority must be set out in the legislation. The structure, name and style of the Authority will be determined essentially by precedent. In some countries with extremely limited manpower resources, it may be necessary to empower a single individual to function in this capacity. It is particularly important to designate the advisory apparatus and to define the circumstances in which its advice must be obtained.
8. The terms of reference of the Authority need to be clearly set out in the law in a way that establishes its responsibilities with respect to the following functions:
(a) require that all medicinal products manufactured in, imported into (including donations) or exported from the country conform to established criteria of quality, safety and efficacy, and that the personnel, premises and practices employed to manufacture, promote, procure, store, distribute and sell such products comply with defined codes of practice and other requirements;
(b) require continued conformity of medicinal products with such standards until their delivery to the end-user;
(c) require that medicinal products are imported, manufactured, exported, stocked, sold, distributed or otherwise dealt with by duly authorized persons;
(d) grant or refuse, after due assessment, licences/authorizations for medicinal products, whether locally manufactured or imported, and whether destined for the national market or for export;
(e) inspect and license/authorize all domestic manufacturing premises, importing agents, wholesalers, distributors, clinics, hospital dispensaries, retail pharmacies and other outlets where medicinal products are sold;
(f) provide for sampling and analytical and other testing of finished medicinal products released into the distribution chain to assure their compliance with approved specifications;
(g) monitor and review the implementation of the legislation; and
(h) ensure that advertising and marketing is in accordance with product information approved by the drug regulatory authority.
Structure of the drug regulatory authority
9. In order to discharge its duties effectively, the Authority must function within an administrative and legal environment that assures its independence of action and its access to effective channels of communication. Procedures should be laid down by which members and staff of the Authority are appointed, their terms of reference and duration of office. Legislative provisions need to be supplemented or complemented by administrative procedures designed to safeguard the independence, integrity, effectiveness and impartiality of the Authority. For instance, administrative or disciplinary rules should specify that members and staff should not be involved in any activity that is liable to create a conflict of interest. To maintain the independence of the Authority, responsibilities for regulation of medicinal products should be administratively and operationally separated from activities concerned with their procurement or distribution.
10. The Authority must exercise its powers independently and impartially. Lawful and bona fide activities and decisions must be protected by conferring relevant empowerment(s)/immunities on staff and others working for the Authority. Conversely, provision must exist to enable affected parties to obtain relief or redress in accordance with national law. The legislation should contain a clause on the need to ensure the confidentiality of sensitive commercial data.
11. The conditions of service, remuneration and working arrangements must be such that vested interests will not be able to exert any undue influence over staff or others working for the Authority to ensure integrity.
Products, personnel, facilities and practices that are subject to regulation
12. Regulatory controls should extend to all medicinal products on the domestic market as well as those destined for export. As most developing countries rely mainly on imports to meet their drug requirements, it is important not only that the imported medicinal products themselves, but also the procedures involved in promoting, importing, storing, distributing or selling them, are regulated by law. Countries with domestic manufacturing capabilities need to ensure that regulations provide safeguards for the quality of starting materials imported or obtained locally either through a licensing process or as part of Good Manufacturing Practice (GMP).
Issuance of definitive product authorization/licence and transitional provisions
13. In countries without a comprehensive system in place for the regulation of medicinal products, legislation provisions must be formulated for:
- authorizing/licensing of all products proposed for marketing after the “appointed date” for the licensing system;
- transitional arrangements to ensure that products on the market before the appointed date can continue to be marketed, within the regulatory system;
- the subsequent review and full registration of products authorized under the transitional provisions; and
- provision should also be made for regulation of renewal of the product authorization/licence after lapse of period for which the licence is being issued.
Product licensing/issue of marketing authorizations
14. The legislation should establish the legal framework under which applications to market medicinal products are submitted to the drug regulatory agency and the procedure for the assessment of applications and the grant or refusal of marketing authorizations. The assessment should be based on defined criteria for safety, quality and efficacy. The legislation should place the onus on the applicant to provide information and data necessary for this assessment.
15. The legislation should provide for regulation determining the amount of licensing/authorizing and renewal fees.
16. A procedure is proposed in the WHO Guidelines for Small Drug Regulatory Agencies (1) under which an inventory is drawn up of all medicinal products on the market before the appointed date and the products have the status of being “provisionally authorized/licensed” until such time as full authorizations/licenses are granted. Depending on the timing of the implementation of legislation, in relation to the appointed day, and the availability of information on medicinal products in circulation, the inventory can be established by:
- including requirements, under the legislation, that manufacturers, importers and distributors of medicinal products who intend to continue to manufacture, promote, import, distribute and sell medicinal products after the appointed date must submit specified information on those products to the regulatory authority, before the appointed date;
- compiling the inventory on a more “informal” basis, from available information (price lists, publications, etc.) and data supplied voluntarily by companies.
In either case the information should be collected in a form suitable for entry into a computerized database such as the computerized drug registration system developed within WHO. This will enable the inventory of products to be organized and sorted for subsequent review (see Appendix 2).
Review of provisionally authorized/licensed products
17. The legislation should establish a framework for the review and assessment of provisionally authorized/licensed products for full registration under the product authorization procedures for new products. The timetable for the review should be stipulated by administrative procedures as availability of resources will determine the pace at which these assessments can be undertaken. Priorities for the review of provisionally authorized/licensed products should be determined normally by therapeutic class and based on health-related priorities established within the national drug policy or national health framework/policy.
18. The legal mandate to ask for the submission of application for re-registration of medicinal products marketed prior to the appointed day should be embodied in the legislation but details of the format and content of applications are, again, best dealt with in regulatory guidelines, to allow greater flexibility.
Authorizing/licensing of manufacturers, importers, exporter, distributors and retail outlets
19. Organizations engaged in the manufacture, promotion, importation, exportation, distribution, sale or supply of provisionally registered or licensed medicinal products must meet prescribed criteria or requirements, regarding facilities, personnel and practices, intended to assure the quality of the product up to the time of usage/consumption. These criteria and requirements must be specified in law. In addition to numerous resolutions of WHO’s governing bodies, several texts developed under the aegis of the Organization offer guidance on the elaboration of such criteria and requirements. They are referred to in Appendix 2.
20. The administrative capacity of the Authority must be complemented by an effective inspectorate suitably trained and mandated to monitor compliance with the legislation. To achieve this it is necessary to liaise with other relevant law enforcement offices attached to related government agencies or authorities and in some countries it may also be necessary to enlist the services of other law enforcement officers. In this case, the law must contain suitable provision to confer appropriate authority on such officers to exercise statutory powers under the law governing medicinal products.
21. Provision must exist to handle recalls and destruction of medicinal products from the market requiring manufacturers to recall unsafe, defective or inappropriately labelled products and, when necessary, to suspend manufacture where facilities or operations are found to be below standard, and to cease unethical promotion activities.
22. The emergence in recent years of counterfeit and other illicit products within domestic and international markets has imposed an extra dimension on the work of regulatory authorities and inspectors. It has also created a need for enhanced collaboration between regulatory authorities, licence holders, customs officials and law enforcement authorities, and for greater vigilance by all persons involved with the manufacture, distribution and sale of medicinal products. Consideration should now be given to legal provisions that facilitate timely and efficient exchange of information between concerned parties, both nationally and internationally, inter alia to counteract illicit trade.
The law must provide a range of specific penalties and other measures to deter violations of provisions of the legislation. Provisions should be included on the right to appeal, or other measures to react to the decisions of the drug regulatory authority.
Monitoring and Evaluation
23. A legislative text containing the above provisions lays the basis for an important administrative system. It is prudent, therefore, that the text should contain provision for oversight and review of the operation of the system. The Authority should thus have as one of its tasks the preparation of general and thematic reports, at periodic intervals, on the state of implementation of the law. These reports should, inter alia, underline deficiencies and weaknesses in the system and propose remedial action. Statutory provision requiring such reports to be tabled before the legislative assembly will ensure that the relevant reports receive due attention.