Definition of responsibilities
As noted above, ultimate responsibility for the marketing authorization function lies with the country’s government. The minimum necessary activities are as follows:
• Establishing and maintaining an inventory of the products available on the local market;
• Premarket evaluation of new products:
- Ensuring that a complete data-set on quality is available;
- Evaluating, as appropriate, either data on quality or relying on a WHO-type certificate (see glossary and Annex 2);
- Ensuring that newly authorized products containing well established drugs are interchangeable (as defined in Annex 3) with locally marketed products, and that the approved product information is accurate and locally useful;
- Issuing a written marketing authorization (or rejection) on completion of the assessment process.
• Evaluating applications to make changes to product information and to pharmaceutical aspects of existing marketing authorizations;
• Noting possible breaches of legislation and referring them to the investigatory arm of the DRA.
In addition to marketing authorization activities, DRA staff may be given responsibilities such as promotion of rational drug use, provision of drug information, control of company promotion, monitoring of adverse drug reactions, publication of information on pharmaceuticals (e.g. a newsletter), and studies of drug utilization to enhance rational drug use and assess the impact of regulatory decisions. In some countries, the cost of a product may be a consideration in reaching a decision on marketing authorization.
As already indicated, resources provided to the DRA for performing marketing authorization activities should be consistent with the defined responsibilities.
Decisions concerning quality, therapeutic equivalence and product information labelling must be taken by persons with suitable knowledge and practical experience of the subject. The quality control of drugs requires a knowledge of pharmacy and chemistry. Evaluation of therapeutic equivalence and product information labelling requires a knowledge of the uses and safety of medicines. As a minimum, evaluators of therapeutic equivalence and product information labelling should be qualified in pharmacy, clinical pharmacology, medicine or a similar discipline, and have practical experience in at least one of these disciplines. It is desirable for evaluators of therapeutic equivalence to have practical experience of biopharmaceutics. While external expertise should also be available (see below), the authority’s own staff must be capable of understanding and implementing the expert advisory body’s recommendations (see below “Expert advisory body”), acting on information made available by WHO or other DRAs as aspects such as safety, and quality, and taking action on their own initiative in a crisis.
Some part of the DRA needs the capacity, including staffing, to investigate possible breaches of legislation and, if necessary, to initiate action in the courts in cooperation with legal officers. A knowledge of the local judicial procedures and legislative process is essential. The DRA itself need not have a full-time lawyer but must have access to legal advice in relation to its functions.
Any organization needs the skills of competent administrators. The scientific and medical experts should be complemented by a suitable number of administrative staff, including computer specialists or access to them. A DRA has a particular need for persons experienced in handling large quantities of documents and daily correspondence, which may need to be retrieved at short notice.
Scientific and medical skills must be continuously updated to keep pace with drug discovery and development, including the development of new means of formulating, controlling and using well established drugs. It is therefore essential for suitable training and practical experience to be offered regularly to the staff concerned. WHO is able to provide assistance in finding places for such training.
The number of staff to be employed in marketing authorization activities should be determined by the responsibilities to be undertaken. The major determinants of staff numbers are these:
• The degree to which the authority is prepared to rely on decisions made, and reports prepared, by well resourced authorities in other countries;
• Whether there is a local pharmaceutical industry in the country, and hence whether there are local products for which a suitable foreign evaluation will not be available;
• The number of products to be processed.
In addition, if there is no current list of pharmaceutical products authorized for marketing, also known as the register, appropriate additional resources will be essential for its preparation.
A regulatory “culture”
The DRA should cultivate an attitude among its staff of independent thinking, impartiality and pride in their work. Everyone in the organization should be motivated by a desire to ensure that effective, safe and good-quality drug products are available to the public in adequate quantities and are used rationally. It should be clear that staff at whatever level who succumb to favours from outside sources are damaging the reputation of the whole organization, including that of their colleagues.
Data submitted by applicants for marketing authorization should be stored with sufficient security to give the applicants the confidence that they cannot be subject to theft or unauthorized copying. To the extent possible, premises should be fire- and water-proof.
Professional staff whose responsibilities include sustained periods of concentration will perform more efficiently (in terms of output and reliability) in quiet surroundings.
Access to earlier documents is essential for technical, legal and political reasons, and must be considered at the time the data are first stored. Electronic archiving has considerable advantages in terms of information retrieval, but is not yet sufficiently durable and reliable. For the foreseeable future, electronic archiving should be backed up by storage of paper copies.
Given the numbers of applications likely to be processed by a DRA, the quantity of information associated with each, and the frequent need for rapid retrieval of information, computerization is the most viable means of recording and keeping track of applications and marketing authorizations. The process of keeping a record of the progress of an application at all stages and of the status of marketing authorizations is known as tracking. These are some examples of the information that a computerized system can provide:
• The progress of a particular application for marketing authorization;
• All premises for which a GMP inspection is due;
• Applications which have been awaiting evaluation for a given period of time, say three months;
• The reference number or date of the currently approved product information;
• Details of previous decisions taken on the same or similar active ingredient;
• A list of marketing authorizations due to expire over the next 12 months.
Applications for variations should also be listed on a computerized system, even if their progress is too rapid for tracking to be valuable. However, this will permit retrieval of information on variations after they have been made.
The country’s register of authorized drug products is most easily maintained in electronic format, The data set can then be quickly searched for information of the type mentioned below under “Inventory of existing products on the market”.
Access to the Internet is of immense value, both for e-mail communication with the staff of other DRAs and to obtain information from web sites. Some well resourced DRAs have a home page which the smaller national authorities will find invaluable as a source of information.
The costs and benefits of computerization are discussed in detail in a WHO document on How to introduce computer-assisted drug registration (2). The WHO manual entitled A model system for computer-assisted drug registration. User manual (3) should also prove useful.
Expert advisory body
In any country, whether or not the DRA has extensive resources, maximum advantage should be taken of local expertise available in universities, research institutes, teaching hospitals and primary health care facilities. This is usually achieved by setting up an expert advisory body which meets on a regular basis to provide advice to the DRA. Membership should include individuals with the highest available scientific expertise so that their advice is seen by the community, health workers and the government as authoritative and credible. The scope of issues to be discussed will determine the expertise required, but it should normally include pharmaceutical chemistry, pharmaceutical technology, pharmacokinetics/bioavailability, pharmacology, clinical pharmacology and medicine. DRAs that intend to evaluate toxicological data will in addition need experts in that area. Members should include both those with up-to-date theoretical knowledge and those with practical experience, especially in quality control, clinical medicine and the conduct of bioavailability/bioequivalence studies. Pharmacists with experience of pharmaceutical distribution, and primary health care physicians, should be included in the expert advisory body to provide practical advice.
If members of the expert advisory body are given membership for a fixed term, their advice is less likely to be dependent on political considerations.
The practical role of such a body varies. Some DRAs seek advice only applications on marketing authorizations concerning new chemical entities. On the other hand, a newer and/or smaller DRA may chose to refer all interchangeable products which are to be evaluated in full to the advisory body, at least until sufficient experience has been gained to serve as precedent and guidance for the future. Equally, a DRA may request the expert advisory body to lay down broad technical policies so that only difficult applications need to be referred. In addition to giving technical advice, such a body can be constituted so that it provides up-to-date information on the local clinical situation, for example in relation to microbial resistance or the prevalence of endemic diseases. The expert advisory body can also be a source of advice as to whether a particular drug is essential in the local context (see below - Rational selection of products), but it is better for this function to be performed by a separate body or committee if resources permit.
It is a matter for local legislation whether final responsibility for marketing authorization decisions lies with the expert advisory body, or with the DRA on advice from the expert advisory body. The legal position, whatever it may be, should be made clear to all parties.
Decisions of the advisory body need to be transparent. In practice, this means that reasons should be given for all decisions.
If the expert advisory body is to review applications for new marketing authorizations or variations to existing ones, it is inappropriate to appoint people who are currently employed by the pharmaceutical industry as members because this would give rise to a conflict of interest. Members should in any case sign a declaration that they have no conflict of interest before participating in the activities of the expert advisory body. Annex 4 contains a model form for this purpose, together with guidelines (for both experts and DRAs) as to what constitutes a conflict of interest.
It should be noted that paragraph 2 of the model statement in Annex 4 allows (among other things) for a member to declare that he or she has a conflict of interest in relation to a particular item in an agenda. The DRA (or the committee’s chairman) may permit the member to withdraw from consideration of that item but remain as a member of the committee for other purposes. Such declarations should be recorded, for example in the committee minutes.
Financial support for the DRA should include provision for the expert advisory body. Expenses may include reimbursement of members’ travel and accommodation costs if incurred. Remuneration for loss of income should not be excessive and should not be related to the outcome of the evaluation.