While many of the elements in Table 1 are so closely linked to the process of drug registration that they logically fall within the task of the Medicines Regulatory Authority, others do not. In well-functioning systems in other countries, one finds that these tasks are handled by other bodies, within or outside the government apparatus. There must however be good communication between all the bodies involved, so that the system functions as a whole. This should be the aim in South Africa.
6.1 The Inspectorate of Medicines
A medicines inspectorate serves to ensure compliance with both the general standards set by the law (for example ensuring that medicines are distributed only through legal channels and in a proper manner) and specific standards for individual drugs set by the control agency (e.g. ensuring that samples of a particular medicine taken from a wholesale or retail outlet meet the quality criteria set in the licence and are accompanied by the approved package insert). For more than a century, some countries have had such inspectorates within the government service. They have enjoyed autonomy from political or commercial influence. It is also widely considered that an inspectorate should also be separate to some degree from the bodies which set standards.
Most or all of the operating costs of the Inspectorate can and should be recovered by charging appropriate inspection fees.
As noted above, the Inspectorate (Sub-directorate: Medicines Control) in South Africa is an understaffed but well-managed body. The arguments for providing the Inspectorate with a degree of autonomy are similar to those applicable to a regulatory authority, .i.e. there must be a means of avoiding interference in its activities and there must be a possibility of providing adequate remuneration.
One possibility is to make the Inspectorate an autonomous body on its own. Another possibility which would provide some economies would be to make the Inspectorate a unit within the autonomous Medicines Regulatory Authority. This possibility is illustrated in Figure 4. As will be seen by comparing Figures 3 and 4, incorporation of the Inspectorate complicates the structure of the MRA, which would in this case have two Directors within its overall framework.
The Review Team is of the view that the development of an autonomous Inspectorate operating within the MRA might be phased in over a period of time but the optimal arrangement should be determined once the MRA is otherwise established.
Since the responsibilities of the Inspectorate are focussed on quality control and compliance, it will be logical to extend its task to include routine monitoring of drug advertising.
A more radical structural approach which has been adopted in a number of countries involves the creation of a general Health Inspectorate. Such a body incorporates specific inspectorates dealing with medicines, prescribers, dispensing practitioners, pharmacists, pharmacies and even the environment. Establishment of such a body, as already exists in a number of other countries, is conducive to cost-effective operation and renders it possible to provide some centralized support, e.g. as regards legal and administrative matters, so that prosecutions can be brought where necessary or other forms of sanctions imposed. Detailed proposals on this matter fall outside the scope of the present review.
6.2 Drug safety monitoring
As noted above, the present Adverse Reactions Monitoring Centre, attached to the University of Cape Town, works only on a small scale, receiving and reviewing reports of suspected adverse drug reactions; the latter are submitted primarily by manufacturers and secondarily by practitioners. One full-time Medicines Control Officer and two part-time staff funded by the Department of Health as members of the Clinical Committee are attached to the Unit; there is also scientific input from University staff.
Monitoring the emergence of risks associated with medicines is a potentially worthwhile activity in most countries, and this is certainly the case in South Africa with its genetically heterogenous population using both orthodox and complementary drugs. It is however only meaningful as a public health activity if:
the Centre concerned succeeds in developing sufficient input of reports to obtain a fair overview of drug safety problems in the country; capacity is sufficient to enable the Centre to overview current problems emerging in the literature and in the practice of other national centres, as well as through the WHO Monitoring Centre at Uppsala, Sweden; the Centre provides output both to the Medicines Control Council (so that restrictive or advisory action can be taken where necessary) and to practitioners, e.g. through a drug information service, so that they can be alerted to emerging risks.
The Review Team is of the opinion that there is merit in having an adverse events monitoring centre attached to a university, where clinical advice can be provided as necessary. The present centre should be maintained, provided its independence can be guaranteed. A structure should be established so that it answers to the Board of the Medicines Regulatory Authority, which should identify a member to liaise with it and to ensure joint review of current developments. In consultation with the Centre, and with the WHO Adverse Drug Reactions Centre at Uppsala a proposal should be developed by the Board to upgrade the UCT centre progressively so that it becomes capable of performing the tasks outlined above.
6.3 Drug information and rational prescribing
As contrasted with the substantial and probably excessive effort which has gone into evaluating and registering new chemical entities in South Africa, too little has been done to come to grips with the need to ensure rational prescribing. From all the evidence available a great deal of prescribing in South Africa is irrational and excessive, and practitioners are almost entirely independent for their drug information on the highly persuasive material emanating from the pharmaceutical industry. It seems very doubtful whether the influence of existing drug bulletins is more than marginal. The overall situation is not conducive to the interests of public health and is frankly wasteful.
The Review Team sees the correction of this situation as a task for the Department of Health rather than the Medicines Regulatory Authority. A commission should be set up to consider how, in the interests of rational use of drugs, an effective drug information system should be developed and financed. Input could be provided by WHO and by the International Network for Rational Use of Drugs (INRUD) which has in the past developed many initiatives in southern Africa. Tools to be used could include the existing List of Essential Drugs and Formulary, the existing drug bulletins (perhaps to be supplemented by or incorporated into an effective national bulletin), and an information centre which provides objective data on request to practitioners. Regional activities could include seminars on rational prescribing. Local activities could comprise promotion of both hospital pharmacy and therapeutic committees and local rational prescribing groups. Here, pharmaceutical representatives would make presentations to groups of practitioners and pharmacists, rather than meeting individual practitioners as happens at present.
It may be noted that in developing a system to promote rational prescribing a great deal can be learnt directly from successful systems abroad, and that much direct input can be obtained from other national bulletins.
Finally, and with regret, the Review Team finds it necessary to stress that existing information centres supported by pharmaceutical companies cannot be regarded as eligible for participation in a future system to promote rational prescribing.
6.4 Drug utilisation studies
Like any other government, that of South Africa is not well informed as to current levels and patterns of drug use. The pharmaceutical industry is generally secretive regarding sales figures and usage surveys; these are in any case usually too superficial to provide insight into aspects of drug use requiring correction, or as a means of monitoring the effects of policy measures.
Well designed drug utilisation studies, e.g. as developed by WHO groups, provide a valuable policy tool at little expense. Such studies can well be promoted by the Department of Health and delegated to interested university groups.
6.5 Licensing of clinical trials
As noted above, South Africa does maintain a system under which permission has to be obtained to conduct a clinical drug trial. This system should be retained and developed. Applications are received by the Registry/Medicines Directorate and handled by a Clinical Pharmacologist who has a full-time appointment as an MCO. In addition, there is a network of Ethics Committees covering most institutions and the bulk of field practice which examine the ethical (and generally also the scientific) defensibility of any proposed trial.
The central system appears to operate efficiently and promptly. So far as can be determined, trials in Phases I, II or III, involving new drugs or the study of new indications are normally submitted for approval. It is not clear however whether all trials are notified in this way. It seems unlikely that so-called "Phase IV" (post-approval trials, which always include a proportion of purely promotional "trials" intended to familiarise doctors with new drugs) are submitted for approval.
The Review Team has consulted only one Ethics Committee, attached to a University Hospital; it cannot express a definite view on standards maintained by such committees generally but they appear to be variable.
The principal question which currently arises is whether the central control of clinical trials proposals should be handled by an MCO attached to the Medicines Control Council or by some other body such as the Medical Research Council of South Africa. The latter is responsible for much medical research in other fields in South Africa, and has issued a book setting ethical standards for clinical research in human subjects, intended primarily for its own units. It has not however expressed any desire to assume responsibility for licensing clinical trials conducted by others. Some further considerations relating to this issue are presented in a supplementary note to this report .
The Review Team considers that there are insufficient guarantees for the maintenance of adequate ethical standards in clinical trials at the present time. The matter needs further examination.
6.6 Access to unregistered products
A procedure already exists for allowing unregistered medicines to be procured and supplied in order to meet the needs of individual patients. Motivated applications are received from physicians, assessed by a Clinical Pharmacologist attached to the present Directorate, and approval commonly can be granted on the understanding that the physician concerned accepts full responsibility for the treatment.
This procedure should be retained with some modification. In particular:
The Clinical Pharmacologist undertaking this work should be attached to the Secretariat, reporting quarterly to the Board of the Medicines Regulatory Authority.
The Board should determine the principles applicable to the assessment of such applications and provide advice and assistance to the assessor concerned in cases of difficulty or dispute.
While it is not unreasonable that the basic expenses involved in supplying an unregistered medicine are met by the doctor or patient concerned, measures should be taken to ensure that the system does not provide a channel for regular commerce in unregistered medicines. Approval should be strictly on an individual basis and be granted only for the quantities needed by the individuals. If the number of applications for a particular drug reach the point where bulk import is required, the supplier in question should be required to submit an application for registration.
6.7 Dental medicines and materials
Medicines used in dentistry are generally modified presentations of those employed in general medicine. They have been, and should continue to be, dealt with by the medicines regulatory system, within which they represent only a minor activity.
Dental materials, such as fillings, are as a rule not used in other areas of medicines, but their mode of investigation and their possible risks are such that they should continue to be dealt with as if they were medicines.
In connection with the above, a dental expert should continue to be attached to the future authority.
6.8 Veterinary medicines
Veterinary medicines are currently the subject of a draft for a National Veterinary Medicines Policy. As regards the law, they were first dealt with to some extent by Act 36 of 1947, sponsored by the Department of Agriculture, which dealt primarily with pesticides but also extended to veterinary antibiotics; registration decisions were to be taken by a senior official of the Department .The Medicines Act 101 of 1965 made no mention of veterinary medicines, but subsequent regulation added them and provided for automatic registration of "old" drugs; new applications were to be handled by the MCC, which established a Veterinary Committee. In neither of the Acts are veterinary drugs optimally defined. The procedures under both Acts remain in force. Confusion has been avoided only by an excellent collaboration between the Department of Agriculture's expert and the MCC's Veterinary Committee.
After consultation with those involved in both Departments, the Review Team fully accepts their recommendation that a single procedure should be adopted to avoid the present duplication. Further suggestions can be found in the supplementary note to the text.
6.9 Cosmetics
Cosmetics containing active pharmacological substances in active quantities (e.g. skin creams with oestrogen) or making medicinal claims should be regarded as drugs and as such subject to normal registration requirements.
Cosmetics not falling within the above classes can raise problems of safety. The Review Team is of the opinion that these should not be handled by the Medicines Regulatory Authority. In most countries which have instituted systems of control they are dealt with by the agencies dealing with foods, commodities and wares; these handle safety issues for a wide range of consumer products and are well fitted to assess cosmetics.
It must be pointed out, however, that the Directorate of Food Control of the Department of Health has already indicated that it would currently have no capacity to handle cosmetics. It therefore seems likely that the problem will only be solved by creating such capacity with the most appropriate group.
6.10 Medicines costs: strategies and cost containment
An increasing number of countries have developed balanced policies to ensure that the sums spent on drugs, particularly in the public sector, are adequate but not excessive. The techniques range from price controls on individual drugs to restrictions on reimbursement from health insurance, as well as efforts to improve the rationality of prescribing (see 6.3. above). Commonly opportunities are found to reduce or modify expenditure considerably.
As a rule it has proved simpler and more effective to develop cost containment systems within health ministries or health services, rather than involving Medicines Control Agencies which have a purely technical task. Introducing price as a criterion of drug approval (e.g. as was for many years the case in France) has been found to be cumbersome.
Further examination of this issue lies outside the ambit of the present Review, but the Team considers that South Africa could benefit from a cost containment programme for drugs, instituted by the Department of Health.
6.11 Medical devices and materials
The intention to regulate medical devices has been an element of policy since Act 101 was passed in 1965. At the present time, compilation of a register of medical devices and materials is entrusted to a single member of the staff of the Directorate. The Review Team is persuaded that this level of input, however consciously carried out, is not meaningful, and that the work should not be continued. The staff member concerned can better be involved in the mainstream of work within the Secretariat of the future Medicines Regulatory Authority.
Some countries have been tempted to establish regulatory and control systems for medical devices and materials analogous to those existing for medicines. The capacity needed to do this effectively should not be underestimated. The products concerned range from condoms and dialysis membranes to X-ray machines; their variety is vast, and many complex devices are not only developed from batch to batch but may even be built to the specification of individual hospitals.
Rather than creating a register, South Africa should consider instituting an information system, entrusted to an appropriate institution in the field of medical engineering. This system would survey the literature (and the regulatory activities of other countries) to detect promptly public health risks associated with medical (or dental) devices or materials. Such problems have for example arisen in recent years as regards certain artificial heart valves (manufacturing defects) and silicone breast implants (leakage of toxic material). The institution concerned could answer enquiries from hospitals and practitioners and also alert the Department of Health to current problems requiring corrective action or the publication of warnings.
Devices which are in effect release systems for drugs, such as intra-uterine devices containing progesterone, must be considered as medicines and controlled as such.
The further development of this approach lies outside the ambit of the present review.
The Review Team finds that there is a degree of confusion regarding the regulations in force. Act 101 of 1965 provides the foundation, but no-one appears to be entirely sure which of the regulations drawn up at various times under the Act are currently promulgated and applicable. Making an inventory and thereafter revising the law and regulations will inevitably take time.
All recommendations in this report are therefore based on working within Act 101 as amended by Act 90/97. It is however evident that at the earliest possible date a new or further revised Act requires to be drafted which reflects the main elements in the new system, and is complemented by regulations to deal with matters of detail. As soon as agreement has been reached on the present recommendations, in their current form or following modification, a small working group involving the transitional MCC, the Department of Health and the Department of Justice should undertake this task so that a new Bill can be presented to the legislature in 1998.
A first essential element in the new Act will be a revised definition of a medicine, as well as an appropriate definition of complementary and traditional products. The current legal definition of a medicine has been variably interpreted and is now the subject of considerable dispute. Foreign legislation provides excellent models.
A second element must be revised criteria for acceptance. In so far as orthodox medicines are concerned these will continue to relate to demonstrated quality, safety, efficacy and the provision of adequate and reliable information. For non-orthodox medicines the criteria of demonstrated efficacy will be replaced by evidence that the medicine is used within a particular philosophy or tradition for particular purposes. The criteria for reliable information will be modified so that claims can be accepted which do not transcend certain specified limits (see above). For orthodox medicines based on well-known and long-established components there will also be an analogous possibility of documenting efficacy, safety and acceptability of claims by documentation from the literature.
A third essential element in the law will be creation of a more appropriate appeal procedure. A phased approach could be as follows:
In dealing with manufacturing facilities for all medicines, the Act should reflect current international standards. The requirement that a pharmacist be responsible for a manufacturing plant might be modified so that responsibility be accorded to an appropriately qualified person.
The Review Team must point out that its own activities regarding reform of the legislation have been impeded by the above-mentioned lack of any overview of the regulations currently in force; once a proper inventory is available, formulation of an adequate Drug Law reflecting both South African and international standards will not be a major task.
Matters to be dealt with by regulation will include the introduction of a revised fee structure.
The current medicines regulatory system in South Africa is funded by the Department of Health. On the basis of the data provided to the Review Team, the total variable cost of the system is approximately 12 million Rand/year. Fees are charged for the registration of products and the income from this source amounts to approximately 5 million Rand/year, although the income does not currently go directly to the Medicines Directorate. A summary of income and expenditure is in Appendix 3. Overall, it is clear that the current budget acts as a considerable constraint on the effective functioning of the Directorate and MCC.
8.1 Fees
The amended Act 101 allows for the fees collected by the registration body to be retained by it. This situation is consistent with a trend internationally for drug regulatory authorities to become either partially or fully cost-recovery organisations. In most of these authorities, the introduction of fees has led to increased capacity of the agency to process applications for registrations in an efficient manner, thus serving the interests of both the public and industry. Industry has been prepared to pay for an appropriate level of what it sees as "service".
A limited financial analysis of the possible impact of changes to fees has been conducted by the Team, but this was hampered by the lack of detailed information. Current fees are structured so that most of the income is derived from evaluation of generic applications. The fees proposed in the new draft regulations might lead to increased income, but this is predicated on the assumption that current workload increases. The changes proposed to fees for applications for NCEs and other types of products are small, and therefore would be unlikely to have a major impact on income in any future structure.
The Review Team believes that the current fees paid by industry to the South African authority are too low. This leads to increased numbers of premature or substandard applications in the system (increasing workload) as well as inadequate income. The introduction of an appropriate scale of fees would have two major effects - providing increased revenue for the agency to do its work and discouraging industry from flooding the system with substandard applications. Industry has indicated its willingness to pay increased fees if this step is coupled to improved efficiency in reviews.
In any future structure that is subsidised by user fees, it will be necessary to allocate budgets for both registration and control functions. Currently, the budget for the Medicines Control Sub-Directorate is approximately 3.5 million Rand/year and the budget for the Registration sub-directorate and MCC combined is approximately 6.6 million Rand/year. The introduction of appropriate user fees could allow as much as a doubling of each of these amendments without any increase in funding from the State.
8.2. External contracts
The current system has formal contractual arrangements with two university-based groups for the provision of services in relation to quality control of medicines. An arrangement also exists for the provision of an adverse drug reaction reporting system, at the University of Cape Town (see Section 5.2 above). Other external work has however primarily been based on direct agreements with individual assessors (e.g. clinicians), even where the latter work within groups.
Current practice provides useful models for future arrangements with the following considerations:
8.3 Reimbursement of members of committees
Currently, committee members are paid for the work done for the MCC on an hourly basis, which is substantially less than can be earned in private practice. This rate is, in the long run, clearly insufficient to attract and/or retain high quality people to do the work. Whilst recognising that it is not necessarily possible or appropriate to pay amounts that are equivalent to private practice or industry contract work, it is important that this system of payment be restructured both to increase the attraction of working for the regulatory authority and to decrease the potential risk of abuse of a time-based payment scheme. There are a number of possible alternatives:
8.4 Financial analysis
The changes in the structure and system that are recommended in this report are likely to lead to complex effects on the number and types of applications processed, and as a result it is difficult to predict accurately the budget that will be available to finance these activities. It is therefore recommended that before firm decisions about fees and funding sources are made, a detailed financial analysis should be carried out. Draft Terms of Reference for this analysis are in the supplementary note.
The implementation of a new system for medicines regulation in South Africa needs to take place as quickly as possible. Whilst the final version of the new MRA may take some months to set up because of legislative constraints, a process should be started to transform the current structure while retaining all necessary staff and expertise. This process will require technical assistance from international organisations and personnel.
9.1 Appointment of an interim council
The current members of the MCC should be released but their participation in developing the new structure will be essential. To allow continuation of essential medicines regulatory activity, an transitional MCC (TMCC) should be appointed as soon as possible. This body should be smaller than the current MCC, include some of the members of the current MCC and be appointed for a fixed term of not more than 12 months. The TMCC will need to meet at least monthly. Its major tasks will be:
the review of applications for NCEs and major new indications that are currently in the system; establishing a multidisciplinary group to assist with processing the backlog of applications (see below); taking other decisions, notably with respect to existing drugs, on matters that are of pressing public health importance; prepare draft standards and operating procedures for the new MRA; contributing to the transition process required for establishing the new MRA.
9.2 Appointment of transitional management
Since substantial changes are needed to transform the current Directorate of Medicines Administration into the Technical Secretariat for the new Medicines Regulatory Authority, immediate management changes are required. Some current personnel may have difficulty in undertaking this task and temporary management may need to be appointed.
9.3 Clearing the backlog
There are backlogs in all types of applications currently handled by the MCC. The Review Team has been unable to establish their exact size because of the administrative deficiencies in the current system. For any new authority to function effectively, this backlog must be cleared. It is recommended that the TMCC in collaboration with the Department of Health immediately establish a group to take on the job of identifying, categorising and devising a strategy to process the backlog of applications. This will require dedicated resources. A definitive target date of not more than 2 years should be set for the completion of this task.
9.4 Establishment of new structure
The new Medicines Regulatory Authority must be in place and operating by the end of 1998. Key matters to be handled in the early phase will be:
The new structure should if possible become operative 2-3 months before the transitional structure is closed down. This temporary overlap will give the new structure the opportunity to undertake some preliminary work (such as the adoption and further development of standards and procedures proposed by the transitional structure) before becoming immersed in a full programme of evaluation and approval.
9.5 Technical assistance requirements.
The Review Team has not attempted to develop a complete list of technical areas where assistance may be required. Areas involved are likely to include professional management, legal drafting and systematic training of assessors in various disciplines, including bioequivalence and therapeutic equivalence. International support should be secured for training programmes in a number of fields. The Review Team considers that such training can most effectively and economically be provided in the form of well-planned and intensive short courses in South Africa. The resources required will need to be considered by the Department at the earliest opportunity.