An official product assessment and registration system for pharmaceuticals exists in each of the 10 countries. Their functions are determined by legal provisions. Systems for registration of pharmaceutical products came into operation at quite different times in the 10 countries - as early as 1942 in Tunisia and as late as 1993 in Uganda. Some of the systems have evolved in response to drug-related crises such as the thalidomide disaster, public pressure to expand the scope of drug assessment and the pressure from industry and consumers to expedite the registration process.

8.1.1 Scope of product assessment and registration

A review of the country reports indicates that each country requires registration of some categories of pharmaceutical products, but not others. Countries define regulation differently, depending on such factors as historical development, major adverse drug accidents, political influence, industry influence and regulatory capacity. For example, herbal medicines are registered in Australia, Malaysia, the Netherlands and Venezuela, but are not registered in Cuba, Cyprus, Estonia or Zimbabwe. In Australia, Malaysia and the Netherlands, the drug laws require herbal and homeopathic medicines to be registered. In Uganda and Zimbabwe, veterinary drugs, but not traditional medicines, are subject to registration.

Assessment and registration are not the same for all categories of products, even in the same country. How extensive the assessment should be depends on a number of factors and varies from country to country. For instance, in Australia, the potential risks of the product and the availability of human resources are taken into account in setting priorities and deciding the depth of the review. On the basis of these parameters, prescription products, some specific alternative products and some medical devices are subject to extensive pre-marketing evaluation and registration to ensure safety, efficacy and quality. Low-risk products are evaluated only for safety. For some product groups, the manufacturer’s declaration of safety is accepted and the product is then subjected to more intensive post-marketing checks, as necessary.

In addition to exemptions based on type, products may also be exempted from registration on the basis of their source. In Cyprus, for example, drugs manufactured or imported by the Government need not be registered. In Australia, drugs produced by unincorporated companies and not traded between states are not registered or controlled. Similarly, drugs for export are not evaluated to the same extent as those sold in Australia.

8.1.2 Changes in scope and process

The scope and process of registration may change over time owing to changes in government policy, political considerations or industry or consumer pressure. In recent decades, three key changes in the registration of pharmaceutical products have occurred in many countries. These are: expansion of the scope of registration; introduction of a fast-track process; and institution of time-limit requirements.

Expansion of scope of registration

New drug laws were introduced in Malaysia in the mid-1980s, which revised registration procedures and greatly expanded the scope of registration. Under the new laws, traditional medicines, veterinary medicines, cosmetics and pharmaceutical raw materials must all now be registered. The new laws were phased in gradually, so that the pharmaceutical industry could prepare for the new legal requirements and regulators could prepare themselves for their additional responsibilities. Implementation of the new laws, which started in 1985, was carried out in four phases. The initial two phases of registration, covering scheduled and non-scheduled drugs, have been successfully completed. The third phase of registration, which started in 1992, covers registration of traditional medicines. The final phase - Phase 4 - covering registration of cosmetics started in 2001. Regulatory control will be extended later to cover medical devices, veterinary medicines and pharmaceutical raw materials.

In Australia, there was considerable political debate about the extension of registration to cover herbal products and vitamin supplements. Politicians who opposed the idea of regulation of non-prescription drugs, as well as those who supported the establishment of appropriate standards of evidence for the efficacy and safety of such products, showed great interest in the issue. In general, consumer groups were in favour of ensuring the quality of non-prescription products, although it has also been suggested that the registration process will hamper the consumer’s right to self-medication. The Complementary Medicines Evaluation Committee was established in 1998 for the further development of appropriate standards for evaluation and registration of non-prescription products.

Fast-track registration

In many countries, a fast-track registration system has been introduced as a result of pressure on the DRA from both the consumer and the client. Consumer groups, especially those involved with HIV/AIDS issues, have demanded that products with potential for the treatment of currently incurable diseases should be approved rapidly. The pharmaceutical industry, eager to introduce new products to the market, has been keen to reduce the costs resulting from delays in registration. In other countries, accelerated registration procedures have been introduced to serve the government’s need to make certain drugs available to the public more quickly.

Fast-track registration systems now exist in Australia, Cyprus, Estonia, Malaysia, the Netherlands, Tunisia and Zimbabwe (see Table 8.1), although probably not all of them were established as a result of political pressure. Different fast-track systems serve different purposes. In Australia, Cyprus and Malaysia, fast-track registration is intended to facilitate the assessment and registration of new drugs for treating serious, life-threatening diseases or conditions. In Malaysia, pharmaceutical entities can be registered for additional indications more quickly. The Netherlands has a fast-track registration system for clones and products qualifying for parallel importation. Estonia allows drugs approved by the European Commission to be registered through its fast-track system. In Tunisia and Zimbabwe, fast-track procedures are linked to government procurement. Each fast-track system is, therefore, a mechanism for modifying regulatory procedures in order to accommodate other government policies.

In Venezuela, there is no official fast-track system. However, “brief-mode” registration is available for generic products for which a bioavailability study has been undertaken. Similarly, Malaysia has an “abridged procedure” for registration of products classified as non-scheduled poisons. This type of simplified procedure does not, in essence, differ from the use of less stringent registration requirements for certain categories of products as seen, for example, for herbal medicines in Australia and the Netherlands.

Time-limits

In many countries the pharmaceutical industry has pushed for time-limits for registration as a means of making regulatory agencies more accountable. The country reports indicate that time-limits operate in all the countries with respect to assessment and notification of the results of applications for registration. However, among the 10 countries, only Australia, Cuba, Cyprus, Estonia, Malaysia and the Netherlands have included time-limits in their drug legislation. In Australia, Malaysia and the Netherlands, different time-limits have been set for registration of different types of products (new chemical entities, generic drugs and fast-track drugs). In Cuba, Cyprus, Estonia and Venezuela, a single time-limit has been set for all products. In practice, the average time taken to register a product containing a new chemical entity (NCE) ranges from six to 19 months, from two to 18 months for generic drugs and from two to six months for fast-track products (see Table 8.1).

Countries vary in their policy towards the application of sanctions if the regulatory authorities do not meet the time-limit for processing applications and notifying the result to the applicant. In Cyprus, the time-limit has been established by legislation, but no sanction is in fact applied if the time-limit is not met by the authority. In Malaysia, there are no statutory sanctions - applicants can only resort to lodging a complaint with the authority. A similar situation applies in the Netherlands. However, in Australia (in the case of a category 3 minor-variation application only) and Venezuela, the drug in question is automatically considered as registered if the time-limit is passed and no official decision has been made. In between these two extremes lies a range of variation. In Cuba, negotiations would take place between the parties involved. In Estonia, the applicant could ultimately take legal action against the DRA, although this has never been done in practice.

Table 8.1 Drug assessment and registration structures and processes

• = Yes = No - = information or data not applicable

In Australia, the authority would have to forfeit 25% of its fee in all cases except that of a minor variation, which would be automatically registered on expiry of the time limit, as described above.

8.1.3 Registration requirements and process

Information required and degree of assessment

Applications for registration of pharmaceutical products are classified in different categories, for example, products containing new chemical entities, generic products, fast-track products, applications for variation and applications for renewal. The requirements for these categories of application differ from country to country and even within the same country. In Australia and the Netherlands, new chemical entities are fully evaluated and dossier requirements are similar to those of the European Union, namely administrative information, chemical and pharmaceutical information, pharmacological-toxicological data and clinical data. In Malaysia, in addition to documentation supporting safety, efficacy and quality, the applicant’s company incorporation or registration certificate, a letter of authorization from the manufacturer (if the applicant is not the manufacturer), a Certificate of Free Sale from the country of manufacture and a GMP certificate are also requested. In Estonia, in addition to submission of documentation supporting safety, efficacy and quality, the applicant must be resident in Estonia.

For non-prescription and generic drugs, the documentation required is simplified and is mostly concerned with chemical and pharmaceutical data. In general, the documentation required for registering products containing new chemical entities is more extensive than that for products in other categories (see Table 8.2). Countries that have the capacity to make an independent assessment of the safety, efficacy and quality of products, such as Australia, Estonia and the Netherlands, do not request the WHO-recommended Certificate of Pharmaceutical Product. Only Cyprus and Tunisia request price information.

Ensuring transparency

Registration requirements, SOPs and decision criteria are documented to ensure transparency of the regulatory process and to facilitate communication between the regulatory authority, the pharmaceutical industry and the public.

While written application forms for registration are used in all countries, only seven countries have a written SOP for staff involved in drug registration (see Table 8.1). In Cyprus, Uganda and Zimbabwe, the absence of a written SOP probably reflects the fact that only a few staff are responsible for registration. In Cyprus, the two pharmacists working in the DCQSS carry out not only registration and licensing, but also GMP inspections. They do not have either a job description or an SOP. In Zimbabwe, a total of nine technical and professional staff perform multiple regulatory functions for the Medicines Control Agency. All 10 countries have documented their criteria for assessing a registration application.

Decision-making

As shown in Table 8.1, all the countries employ an expert committee to support their assessment of applications for registration. The structures and roles of the committees vary between the countries, however. Those drug regulatory authorities with a board or a mixed/hybrid structure possess final decision-making powers, while for drug regulatory authorities with a departmental structure, the final decision-making power normally rests with the head of the department, unless it is delegated. In Australia, the legal power to make the final decision resides with the Secretary of the Department of Health. However, the Secretary has delegated the decision-making authority to senior technical staff within the TGA.

Table 8.2 Technical information and documentation required for registration of products containing new chemical entities

• = Yes = No

Registration validity and review

Once an application has been approved for registration, an official document is generally issued to the applicant upon payment of a registration fee, to prove that the drug may be sold. The period of validity of the registration licence or certificate varies. Australia and Zimbabwe allow a “life-long” licence, while other countries set a time-limit. In Australia and Zimbabwe, mechanisms other than licence renewal are used to evaluate the product. In Australia, a new product is reviewed for safety every year during its first three years on the market. Thereafter it is reviewed if a new application is made or a question of safety arises. In Uganda and Zimbabwe, an annual retention system operates for all registered pharmaceutical products (although documentation is not reviewed). If the retention fee is paid late or not at all, fines will be imposed or the product removed from the registry. In all the countries, registration agencies have the authority to initiate a change in the registration status of a pharmaceutical product. In other words, they can take regulatory action following evaluation of an individual drug or product category (see Table 8.1).

Appeals system

There is an appeals system for resolving disputes about registration decisions in each of the 10 countries. Some countries have a number of levels of mechanism for the settlement of disputes. Under these systems, the first step is usually submission of a complaint to the registration body or the supervisory body for a new ruling. If the new ruling is not satisfactory, the case can be forwarded to another level, which may be an independent administrative court, as is the case in Australia, Estonia, the Netherlands and Zimbabwe. In others, the registration body and/or ministry also has the power to determine whether the previous decision should be overturned (see Table 8.3).

Table 8.3 Appeals system