The present review of the medicines regulatory system in South Africa was conducted during the period January-March 1998. The members of the Review Team, their curricula vitae and the approach taken to the Review are listed in Appendix 1.
The need for a review was agreed between the Minister, the MCC and the Department of Health in mid-1997 as part of the ongoing process of review and reform of health systems in South Africa that had been occurring since 1994. It was decided that a team should undertake the review and that the team should consist of two international experts in medicines regulation and a person from South Africa with knowledge of the system who had not previously been involved in it. Members of the Department of Health would provide support and resources for the review. The South African Drug Action Programme (SADAP) was asked to identify appropriate external consultants.
Potential international and national consultants were approached in late 1997 and three proposed by SADAP were accepted by the Minister. SADAP was asked to assist in supporting the review process and agreed to do so. The selection of the team was finalised in late December 1997, including the appointment of a member from South Africa, and the Team then commenced the review in January 1998.
The Terms of Reference approved by the Minister of Health (Appendix 2) provide a very wide basis for considering all aspects of the control of medicines and related products, but with emphasis on the procedures for admitting medicines to the market. In carrying out its task, the Review Team drew up an inventory of all those matters which can reasonably be considered to form part of a country's overall approach to these products (Table 1). This list makes it possible to consider systematically how and where these various matters have been handled up to the present and how they might be dealt with in a future system.
As noted in the Appendices, the Review Team consulted many of those involved in the regulatory process, either as staff or as Council members. It also received many written submissions providing both information and views. These contacts proved very valuable. Much of the present report reflects information and opinions which were laid before the Team in this way. The Review Team undertook its task conscious of increasing workloads and demands for prompt and consistent handling of submissions.
For the sake of clarity, the main text of this report is purposely kept brief. At the end of the report the reader will find a series of supplementary notes which provide further information on some topics and indicate in greater detail how the various issues can be handled. The numbers appearing as superscripts in the text refer to these notes which are found in the Section "Supplementary Notes".
The Review Team is confident that the changes proposed in the present report are feasible. They reflect and incorporate changes that have occurred in many drug regulatory agencies internationally, particularly over the past 5 to 8 years. They will result in the emergence of a medicines regulatory system attuned to the special needs of the people of South Africa.
2. Strengths and deficiencies in the present system for registration of medicines
The system that currently exists in South Africa was established by law in 1965. It is based on the combination of a technical secretariat (the current Directorate of Medicines Administration) located within the Department of Health, and an external expert advisory group (the current MCC). Most of the technical aspects of evaluation of applications for registration of products are handled externally (by the MCC and its various committees). Aspects of medicines regulation that relate to inspection and control functions are primarily handled by the Directorate.
It is instructive to compare the existing structure with regulatory practice as it has developed in other parts of the world. There have been many recent developments in the field of drug regulation; most key authorities have been reviewed and restructured to a greater or lesser extent. Particular issues considered have been the need to harmonise formats for submissions, the issue of mutual recognition of registration decisions, and the impact of the introduction of fees for registration applications.
In general terms, the functions of any medicines regulatory authority (MRA) fall into two main groups. These are (1) the processes that lead to the registration and legal supply of new medicines, and (2) the processes that allow inspection and control of products once they are on the market. There are various ways of structuring a MRA to allow these functions to be carried out: the entire authority can be an independent, para-statal structure (eg the UK), or the entire authority can be a unit within a ministry of health (eg Australia). If it is considered preferable, the inspectorate/control functions can be separated from the medicines evaluation functions (eg Sweden, the Netherlands). The inspectorate and control functions are in fact nearly always the province of a Government Department, though they often enjoy a degree of autonomy.
The scientific evaluation of submissions, which is basic to drug registration, can also be carried out in different ways: largely "in-house" (eg the UK and the USA), or entirely externally (Norway, Belgium) or using both internal and external expertise (Australia, the Netherlands). The use of external expert advisory committees in the evaluation process is very common.
Policy development in relation to supply, access to, and use of medicinal drugs is rarely the responsibility of a MRA. (See Section 3(vi) and Section 4 below). Technical issues in relation to policy may however be considered by a MRA at the request of the Minister of Health. In some countries, a separate policy advisory group is appointed, and this group usually includes representatives of all stakeholders, including industry, consumers and the MRA.
2.1 Strengths
The South African medicines regulatory system in the past has been well regarded internationally in terms of its approach to the evaluation and registration of medicines. Two aspects of the current system are particularly effective and should be maintained and enhanced in any future system.
The use of external evaluation groups and committees with peer review has been a particularly effective way of using available capacity and expertise, as well as involving health professionals beyond the Directorate, Medicines Administration in the process of medicines regulation. There are many advantages in having evaluations of technical matters carried out by experts who are medically and scientifically active in their fields. In some areas (e.g. pharmaceutical chemistry and clinical trials), effective links between the staff of the Directorate and external evaluation groups have developed that have helped to expand capacity within the Directorate. In any future structure, the principle of external evaluation groups should be maintained, but the work should be more widely distributed amongst all tertiary institutions. A systematic process to recruit and train new evaluators should be introduced.
A key function of the medicines regulatory system in the past and current environment in South Africa has been the inspection of manufacturing and supply premises. In spite of considerable constraints, the Inspectorate (the Sub-Directorate of Medicines Control of the current Directorate of Medicines Administration) has over the past three years been able to develop internal capacity, adopt a systematic approach to the inspection and control needs of the regulatory system and maintain international standards. Although the Inspectorate has some way to go, the development process continues. In the future system, the Inspectorate should be maintained and further enhanced.
2.2 Deficiencies
The Review Team initially sought to consider whether the present system of medicines regulation has, broadly speaking, adequately served the interests of public health. For a series of reasons it concludes that the achievement has been very variable, both in scientific and administrative terms. The variation in standards can be attributed to a number of identifiable deficiencies in the system; some have existed for a long period, others have become acute only recently.
In assessing deficiencies in the current medicines regulatory system, the Team has, as noted in Section 1, considered information from many sources, both within and outside the system that currently exists. We do not intend to consider individual cases and disputes, as we do not believe this will assist the process of rebuilding a medicines regulatory authority to meet South Africa’s current and anticipated needs. However, it is clear that the current system has been under stress for some time and has become unable to meet those needs. The key deficiencies are set out below.
(i) Communication.
Communication between all parties involved in medicines regulation (the Directorate, Department, Minister, the MCC, general public and industry) has deteriorated to the point that it is entirely inadequate or confused. We have identified many reasons for this, including lack of effective formal channels of communication, the development of significant distrust between individuals and groups involved in all aspects of the process, and the lack of understanding of the need for effective communication. The breakdown in communication has become so severe that we do not believe that it can be remedied in the current structure.
(ii) Confusion of roles and responsibilities
The roles of the MCC and the Directorate in the process of medicines regulation are no longer clearly understood by those involved. The confusion of roles is compounded by the fact that the current Directorate is obliged to play two different roles, acting for the Department on the one hand and the Council on the other. The Registrar may on some occasions write letters to the Director even though these functions are exercised by one and the same person.
Policy development has become a major part of the MCC’s considerations. At times it has resulted in Council’s being distracted from its primary task of evaluating medicines. The Directorate has attempted to fill the resulting gap, but without sufficient resources, which has resulted in accumulation of backlogs, increasing pressure on staff, and the occurrence of significant variability in the standard of decision-making. As the overall system is under significant stress, it has lost the ability to respond appropriately to crises, or to develop new ways of regulating in response to changes in policy. We do not believe that it is possible to redefine roles and responsibilities appropriately without major changes to the current structure.
(iii) Administration
Efficient administration and appropriate management are essential for any public sector structure. The Team has identified many and serious problems in this regard in the current medicines regulatory system, notwithstanding the good intentions of personnel involved. There is lack of insight into modern management techniques. This has resulted in failure to use appropriate information technology, lack of adequate administrative support systems to meet the needs of handling large quantities of data, lack of mutual recognition of skills and expertise, inconsistent approaches to personnel management and lack of capacity to respond appropriately to a changing public health environment. Much of this situation is related to the confusion of roles and resulting stresses on the system discussed above, but it is also due to entrenched behaviour patterns and ways of operating. In order to remedy this picture, there again need to be major changes in management structures and administrative systems as they currently exist in the Directorate for Medicines Administration and MCC.
(iv) Concentration of influence within particular groups
Any regulatory authority which delegates tasks to particular external groups of experts or to sub-committees over a long period runs certain risks. While these groups constantly acquire more experience and knowledge, and therefore become ever more indispensable to the authority, they also acquire a considerable influence on the system as a whole. This influence can actually render it difficult at a given moment to redistribute tasks so as to involve a wider spectrum of groups and experts. A further consequence may be that the groups acquire such authority that other experts routinely defer to them, hence impeding balanced discussion. Finally, if the various parts of an application are essentially assessed by different groups (e.g. pharmaceutical versus clinical) there may be little opportunity for interdisciplinary debate on the file as a whole.
These risks have manifested themselves in South Africa. The number and influence of committees has constantly grown, and many essential decisions are essentially taken there rather than in the MCC. In addition, a very small number of University centres have acquired great authority. Little or no effort has been made to involve other centres, such as those where the formerly underprivileged population groups are at centre stage.
To remedy these situations requires on the one hand a simplification of the committee structure and on the other a deliberate programme of recruitment and training to broaden the basis of the authority's operations.
(v) Conflicts of interest
A medicines regulatory authority exists to serve the public health interest, and no other. Inevitably however, its most intensive day-to-day contacts are with the pharmaceutical industry, the interests of which do not always run parallel with public health needs; individual experts are also likely to be confronted daily with industrial activity and some inevitably have a degree of financial involvement, e.g. in the sense that some of their own scientific research receives industrial support. For such reasons, well-reputed foreign agencies have developed strict written rules with respect to situations in which conflicts of interest could arise. Such rules apply to both individuals within the organisations and the organisations themselves.
For reasons which are not entirely clear to the Review Team, no such concrete rules have ever been put into effect in South Africa. A document setting out some applicable principles was approved by the MCC in 1996, but we have found no evidence that it has been implemented in practical terms. In this highly sensitive field it is as necessary to avoid a situation in which improper influence might be suspected as one in which it actually exists.
(vi) Technical capacity
Partly as a result of the concentration of influence in a few centres, there has been limited recognition of the need for technical expertise in some areas relating to medicines regulation. Highly technical areas such as evaluation of bioequivalence have been poorly developed, which is of particular concern given the increasing need for high quality generic medicines, in the evaluation of which the essential question is usually whether they are fully interchangeable with existing medicines.
Post-marketing quality control, and sampling and analysis of products in support of the Inspectorate’s activities, has only recently begun to be considered systematically. At the present time there appear to be a number of small control laboratories trying to do this with only limited national coordination.
It is not clear that toxicological and animal pharmacological data always receive sufficient attention since clinical assessors are not necessarily trained to review material of this type. This problem seems to exist both in regard to the assessment of applications for clinical trials, and at the phase when new drugs are evaluated.
The existing academic capacity for external evaluation work is also now under threat from two sides. On the one hand, the volume of business being transacted by the Council is rapidly increasing. On the other hand, pressure on university staff within certain institutions which have long experience in this field is increasing as a result of restrictions to their funding., There is no doubt that the concept of public duty and the educational value of such work will continue to play a role in attracting both Council members and assessors, but the call for a realistic level of remuneration either to individuals or directly to universities is going to become imperative. Unless it is met the evaluation system could collapse in the foreseeable future.
(vii) Non-orthodox (complementary and traditional) medicines
As noted above, there is no provision under the present law for dealing with the large and growing field of complementary and traditional medicines. Medicines control clearly needs to be extended in an appropriate manner to this field, aiming to ensure that no unsafe products are on sale and that the texts attached to such products do not encourage irresponsible use. In the future medicines control system, there will need to be a systematic attempt to deal with this area fairly, having regard to both public health considerations and public demand.
(viii) Development of capacity
Again as result of the concentration of influence in too few centres, there has been a lack of a systematic approach to training and the development of capacity for medicines regulation in South Africa. Recruitment and training of new evaluators has been on an ad hoc basis. Institutions have not taken measures to create more capacity because within the institution, the existence of the evaluation groups is hardly recognised.
The appropriate use of existing technical capacity is of equal concern to the Review Team. For example, in some situations, staff of academic level are obliged to spend a disproportionate amount of time on non-scientific work because of the lack of mid-level support staff. It is not unreasonable today to expect a highly qualified expert to deliver his/her texts or letters in draft on a word-processor, but he/she should not be obliged to handle filing, photocopying, mailing and telephone enquiries more than incidentally.
(ix) Incorrect priorities
To use limited capacity and resources effectively, priorities must be carefully chosen with regard to current public health needs, and to opportunities to benefit from experience in other parts of the world. This has not consistently happened. A notable example concerns the massive effort devoted to assessing drugs based on new chemical entities, despite the fact that these have often been assessed earlier by reliable agencies in other countries. This is in sharp contrast to the level of effort devoted up to the present to the evaluation of medicines listed on the EDL and generic products.
Similarly, resources available for international contacts and travel have been insufficiently devoted to the purpose of mobilizing the necessary contacts in this regard.
3. Constraints and conditions for change
Medicines Control is governed primarily by the Medicines Act of 1965 (Act 101) and by a series of regulations. Although the Act has recently been amended, this was prior to the present Review. It will need further revision to provide the appropriate legislative framework for the new system recommended in this report. More immediate steps will necessarily have to be taken within the frame work of the present law, though adapting its interpretation and providing new regulations as necessary (see Section 7, below).
The strengths of the present system must not be endangered; effective processes must be continued without interruption. From the start, too, loyal individuals doing good work must be motivated to continue and to be involved actively in implementing the new system.
On the other hand some processes, which in their present form are not serving the public interest, can be discontinued at once, thus releasing capacity for other work.
The process of reform will be facilitated if some persons who are very closely identified with the present system are released to undertake other tasks in the health sector. The names of the persons concerned will be furnished separately to the Minister.
Whereas most of the changes proposed in this report can and should be implemented immediately or in the very short term, those demanding acquisition of particular skills will inevitably demand more time. In particular, the principles of affirmative action can only be served if promising individuals in hitherto underprivileged population groups are systematically given the opportunity to gain knowledge and experience in this highly specialized field.
Because the field of medicines is highly commercialized it is characterized in every country by extreme pressures on the control system and intensive lobbying at every level. There are also tensions between adherents of various schools of treatment. In the South African situation these pressures have developed to the point where there is very widespread mistrust. As change is introduced it will be vital to demonstrate that the only intention is to serve the public's proven and perceived health interests fairly and efficiently. In this complex field, genuine mistakes will inevitably be made and some decisions will be disputed, but there must be sufficient openness to ensure that there is no opportunity to develop hidden agendas or act from improper motives.
There must be a very clear separation of responsibility for policy in the field of medicines and for technical activities in this area. The former must lie with the Minister of Health and the Department of Health (see Section 4 below), the latter with a series of bodies specially constituted for this purpose, primarily the drug regulatory authority (section 5) and the Inspectorate of Medicines (Section 6.1)
Policy in relation to the entire field of medicines will lie with the Minister, advised by the Department of Health.
The Review Team suggests that consideration be given to the institution of a standing advisory body to the Minister on issues of drug policy. This is a complex field in which the many different aspects catalogued in Table 1 of this report commonly need to be viewed together, with activities in one specialised area complementing those in another. The present Drug Policy Forum has served primarily to provide information to the various parties concerned. A small policy advisory group, by contrast, might bring together representatives of the professions, consumers and industry in order to consider both specific and general issues and to assist the Minister in developing measures to deal with them.
5. Principal elements in a new regulatory system
There is no real doubt that South Africa is capable of creating and sustaining a world-class system for the regulation of medicines. Quite apart from the fact that there have been considerable achievements in this country over a period of 33 years, one may point to the fact that various much smaller countries attain this standard. This is the case, for example, in Scandinavian countries with populations of only 4 to 6 million each, and only 2 to 4 university centres in each of them. While South Africa faces particular problems resulting from low average incomes and tax revenues, these can be compensated for by exploiting the opportunities which now exist for reputable national agencies to collaborate, share work, and rely upon one another.
5.1 Need for national regulation
In view of the growth of international and regional agreements concerning drug regulation, the need for maintenance of national systems for the regulation of medicines is sometimes questioned. The Review Team is firmly of the opinion that in South Africa a national system must be maintained, and that this situation is likely to pertain for the foreseeable future.
5.2 Principles
The Review Team proposes the establishment within the immediate future of a new Medicines Regulatory Authority (MRA) to replace the system existing at present. Bearing in mind, however, the need to work for the present within the existing Act 101 as amended by Act 90/97, some titles for bodies and posts will remain unchanged. This need should not obscure the fact that one agency is being replaced by another; experience shows that this is the most effective means of introducing fundamental change without delay.
5.3 Status
The Medicines Regulatory Authority will be an autonomous parastatal organization which in principle will be largely but not completely self-financing. By virtue of its receiving a partial subvention from government funding it will be protected from complete reliance on income from commercial applicants.
One essential element in autonomy is that decisions cannot be overruled for political reasons. It is however essential to create a proper appeal procedure for applicants. (See Section 7 and corresponding notes.) Abuse of power or procedural irregularities must be amenable to corrective action by the courts.
The exact status of a parastatal agency must be determined in consultation with the Department of Justice; in particular, the status of the staff with respect to public service regulations and duties needs to be defined, and rules set regarding the provision of gratuitous or subsidised facilities (accommodation, communications) by the state. Some autonomous agencies (e.g. in The Netherlands) are accommodated free of charge in Departments of Health, others (Sweden, Uganda) operate from their own premises as would independent corporations.
5.4. Roles
The new Medicines Regulatory Authority will be concerned only with the technical regulation of medicines and remedies, and not with issues of policy.
It will be charged with applying and interpreting the law both in order to assess the acceptability of individual medicines (or claims for particular applications of existing products), and in order to develop more detailed standards for particular purposes.
5.5. Structure
An organisational plan for the Medicines Regulatory Authority is outlined in Figure 3. The Medicines Regulatory Authority will comprise:
A Board of Management, responsible for maintaining and advancing technical and managerial standards. The Board will be appointed by the Minister on the advice of the Department of Health. It will include representatives of the principal scientific disciplines involved in its work as well as representatives of complementary and traditional medicine, consumer interests and a representative of the Department of Health. The Director and the Chairmen of the two Expert Technical Committees will be non-voting members. A managerial expert and a lawyer may be co-opted if necessary. The Minister of Health will be eligible to attend any meeting of the Board.
The Board will receive and handle documented decisions on technical matters from the two Expert Technical Committees (see (d) and (e) below. It will formally accept these decisions, but may exceptionally stay them if it believes there has been procedural error, or refer them back for reconsideration if it questions their technical validity.
The Board will, with the assistance of the Technical Secretariat, and in consultation with the Expert Technical Committees, formulate and adopt operating procedures for the Authority as a whole and its component parts.
The Board will similarly, with the assistance of the Technical Secretariat, and in consultation with the Expert Technical Committees, formulate and adopt technical guidelines for the Authority as a whole and its component parts.
The Board should make provision for the re-assessment of registered medicines, including consideration of new evidence of adverse effects and interactions. To this end, the Board will ensure input from the Adverse Reactions Monitoring Centre (see Section 6.2) and promote its development.
As part of the Authority's operating procedures, the Board will set rules as to which technical tasks can be performed by staff attached to the Secretariat rather than being entrusted to external assessors.
The Board will assist the Director in appraising the performance of technical staff working within the Secretariat and in developing the capacity and capabilities of the staff.
The Board will determine how Ministerial directives on policy issues can most effectively be interpreted insofar as they relate to the field of work of the Medicines Regulatory Authority.
The Board will ensure that a monthly technical report on current work is issued by the Authority for general distribution and that a quarterly report on the Authority's status, progress and activities is prepared for the Minister of Health.
The Board will be the body responsible for general communication between the Authority and the Minister of Health, industry as a whole, the professions, the public, the media, other national agencies and international or regional organizations active in the field of medicines control. On specific issues it may choose to delegate this task in whole or in part to the Director as head of the Technical Secretariat.
A Director, appointed by the Board subject to the approval of the Minister who will be responsible for day-to-day operation and will be head of the Technical and Administrative Secretariat (see c) below).
A Technical and Administrative Secretariat providing support to the Board and the Committees and maintaining contact with applicants.
A First Expert Technical Committee (ETC1) to handle all matters relating to orthodox medicines. The Committee will comprise experts from the relevant scientific disciplines as well as an appropriately qualified Technical Secretary; the latter will head a technical support group within the Secretariat and will attend committee meetings as a non-voting member.
A Second Expert Technical Committee (ETC2) to handle all matters relating to non-orthodox medicines. The Committee will comprise experts representing the principal schools of traditional and complementary medicine, as well as an appropriately qualified Technical Secretary; the latter will head a technical support group within the Secretariat and will attend committee meetings as a non-voting member.
5.6 Standards
Scientifically based medicines will continue to be evaluated according to the four generally accepted criteria of quality, safety, efficacy and the provision of adequate information for the prescriber and user as reflected in the existing Act 101.
Medicines and remedies formulated according to the philosophies or beliefs of the various schools of complementary and/or traditional medicine will be assessed only with respect to quality, safety and the provision of adequate information for the prescriber and user; they will carry a declaration that they are formulated according to the philosophies of a particular school, or "are traditionally used for...." particular purposes. Lists of claims or indications will be assessed against a general guideline to be drawn up by ETC2 and approved by the Board.
In either class, medicines will be evaluated primarily on the basis of data submitted by the applicant, whether these comprise the results of original research or material from bibliographic sources; the committee concerned will however also evaluate each application in the light of its own knowledge and experience.
5.7 Priorities
Deviating from past practice, the new Medicines Regulatory Authority will establish priorities in its work which are in accordance with current national needs. In doing so, it will make the best use of nationally and internationally available resources. In particular:
5.8 Confidentiality versus freedom of information
Files submitted to the Medicines Regulatory Authority by an applicant may contain certain proprietary and commercially sensitive data, particular those relating to the mode of preparation of drug. Data of this type shall be treated in strict confidentiality by the Authority, its Board and Committees, its assessors and the secretariat.
Confidentiality provisions render it necessary to obtain written commitments from all those involved whether as staff members or external experts.
To provide open and transparent information about decisions taken on applications for registration, the Board’s decisions and the relative motivation will be published in the monthly report (see Section 5.5). The degree of detail to be provided will be a matter for further discussion.
5.9 Avoidance of conflicts of interest
Members of the Board and of its Committees, as well as external assessors, should be obliged to declare in writing any conflict of interest which they may have in terms of their receiving either short- or long-term support from a commercial company in the field of pharmaceutical, complementary or traditional products. Such support could include payments relating to the activities of a unit, or fees for the conduct of a specific study with a product. It will then be possible to ensure that the persons involved do not engage in assessment or discussion of issues relating to the specific company or product.
Owners or employees of companies active in these fields, or long-term consultants for such companies or associations of such companies, will not at any time be eligible for membership of the Board or the Committees or for involvement as assessors for the Authority.
Appointment to the Chairmanship of the Board or of the Committees will similarly be conditional upon the appointee meeting the above requirements, but also upon his or her receiving no financial support from commercial interests in any other form for the operation or equipment of university or other units under his or her control.
To avoid undue influence or lobbying by industrial firms or applicants at the level of internal or external staff, Board or Committee members or assessors, procedures binding on these persons or on applicants will need to be developed by the Board. Generally speaking, administrative aspects of an application should be discussed by an applicant only with the Director or his designated deputy or liaison officer, and technical matters only during formal hearings. Direct contact with individual assessors should be rigorously avoided.
5.10 International activities
The Board will develop rules regarding participation in international activities in its field of operation. These rules should provide for a degree of work-sharing with other agencies and for the establishment of sufficiently close contacts to ensure that South Africa benefits from international initiatives.