The regulatory regimei Classification
In terms of the Medicines Act, the term 'medicine' is broadly defined to include a substance (or mixture of substances) used, manufactured or sold for use in the diagnosis, treatment, mitigation, modification or prevention of disease or for restoring, correcting or modifying any somatic or psychic, or organic function in humans, and which includes any veterinary medicine.
The term 'complementary medicine' is broadly defined to include a substance (or mixture of substances) that originates from plants, fungi, algae, seaweeds, lichens, minerals, animals or other substances determined by the Authority and is used, manufactured or sold for use in maintaining, complementing or assisting the physical or mental state; or in the diagnosis, treatment, mitigation, modification, alleviation or prevention of disease or illness or the symptoms or signs thereof or abnormal physical or mental state of a human or an animal.
CAMs are classified into sub-categories based on whether they constitute discipline-specific medicines (with such disciplines as may be determined by the Authority) or health supplements.
The term 'medical device' is broadly defined in the Medicines Act to mean any instrument, apparatus, implement, machine, appliance, implant, reagent for in vitro use, software, material or other similar or related article, including certain hazardous substances intended by the manufacturer to be used, alone or in combination, for humans or animals, for one or more of the following purposes such as the diagnosis, prevention, monitoring, treatment or alleviation of disease or injury, the investigation, replacement, modification or support of the anatomy or of a physiological process; supporting or sustaining life; control of conception; disinfection of medical devices; or providing information for medical or diagnostic purposes by means of in vitro examination of specimens derived from the human body; and that does not achieve its primary intended action by pharmacological, immunological or metabolic means, in or on the human or animal body, but that may be assisted in its intended function by such means.
The Foodstuffs, Cosmetics and Disinfectants Act 54 of 1972 (the Foodstuffs Act) defines a 'foodstuff' as any article or substance (except a medicine as defined in the Medicines Act) ordinarily eaten or drunk by a person or purporting to be suitable, or manufactured or sold, for human consumption, and includes any part or ingredient of any such article or substance, or any substance used or intended or destined to be used as a part or ingredient of any such article or substance.
Consequently, if a product is a medicine, as contemplated in the Medicines Act, by definition it cannot be a foodstuff. Foodstuffs are not subject to any registration process in South Africa, however, the labels of all foodstuffs must comply with the provisions of the relevant labelling regulations, as well as any guidelines published thereunder.ii Non-clinical studies
The National Health Research Ethics Council, which was established under the National Health Act 61 of 2003 (the National Health Act) is, inter alia, authorised and mandated to set norms and standards with respect to research conducted on animal and human subjects.
In terms of the General Regulations to the Medicines Act, as amended (the General Regulations), persons desiring to initiate or conduct a clinical study are required to apply to the Authority, in the prescribed form, for authorisation to conduct such a clinical study.
Other legislation, guidelines and standards that must be taken into account when clinical studies are initiated and conducted include the Animals Protection Act 71 of 1962, the South African Medical Research Council's (SAMRC) Guidelines for Ethics of Medical Research: Use of Animals in Research and Training, and the South African Bureau of Standards' South African National Standard for the Care and Use of Animals for Scientific Purposes.iii Clinical studies
No person may conduct a clinical study without the authorisation of the Authority.
Clinical studies in respect of living persons must comply with the provisions set forth in the following:
- the National Health Act and the Medicines Act, and the regulations thereto; and
- regulations, guidelines on ethics and professional standards and other norms and standards set by institutions such as the Department of Health, SAMRC and relevant Research Ethics Committees (RECs) such as the National Health Research Ethics Council, in respect of procedural and substantive matters.
In terms of the General Regulations, persons desiring to initiate or conduct a clinical study are required to apply to the Authority, in the prescribed form, for authorisation to conduct such a clinical study. Such application must include, as a minimum, the clinical study protocol, the investigator's brochure, details regarding the investigators, supporting documents regarding the qualifications of the investigators, study insurance, professional indemnity insurance, participant information forms, informed consent documents and the approval by the relevant REC.
All clinical studies must be conducted in accordance with guidelines for good clinical practice as may be determined by the Authority from time to time.
The person authorised by the Authority to conduct the clinical study is further required to submit milestone and special reports to the Authority. Notwithstanding the latter, the principal investigator is also required to inform the Authority of any suspected adverse events, or safety concerns, occurring as a result of the use of any medicine during the conduct of a clinical study.iv Named-patient and compassionate use procedure
Access to unregistered pharmaceutical products may be achieved by means of submitting an application to the Authority in terms of Section 21 of the Medicines Act.
Although the Authority is empowered to authorise the supply of an unregistered medicine, this power is only exercised in emergency situations, in which case the requesting entity will be required to record the names of those persons to which the unregistered medicine is being supplied.
Section 21 Applications are generally made on a named-patient basis and must be initiated by the patient's treating physician. The Section 21 Applications must be on in the prescribed form and, inter alia, set out details regarding the unregistered medicine. A duly completed and witnessed informed consent document is also required.
The person under whose supervision the unregistered medicine is prescribed, is required to submit a progress report to the Authority no later than six months after the commencement of the use of the unregistered medicine, or earlier if requested.
In addition, reporting in respect of the outcome of the treatment, as well as any adverse drug reaction, is required. A further progress report must be submitted to the Authority within 30 days after the completion or termination of the use of the unregistered medicine.
In the case of unregistered biological medicines, the Authority may require that:
- the number of samples of every batch, together with one copy of the protocol in respect of the testing of the bulk batch and filling batch and one copy of the certificate of release issued by the competent authority in the country in which the biological medicine was manufactured, be submitted to the Authority as a batch release condition; and
- at least the number of samples of every batch, together with one copy of the protocol in respect of the testing of the bulk batch and filling batch of the biological medicine manufactured in South Africa, be submitted to the National Control Laboratory of the Authority, as a batch release condition.
The Medicines Act provides that, save for certain limited exceptions, no person shall sell any medicine that is subject to registration by virtue of a declaration published, unless it is registered.
The definition of 'sell' includes to import, offer or supply or dispose of a medicine to any person whether for a consideration or otherwise.
In principle, and in respect of a specific product, if the product falls within the broad definition of a medicine it will be subject to compulsory registration in terms of the Medicines Act if it is in a class or category of medicines that has been called up to registration by the Authority in terms of Section 14(2).
In terms of the Medicines Act, every application for the registration of a medicine, medical device or in vitro diagnostic (IVD) devices shall be submitted to the Authority in the prescribed form and shall be accompanied by the prescribed particulars, samples of the relevant medicines and the prescribed registration fee.
If the Authority is satisfied that the medicine is suitable for the purpose for which it is intended, complies with the prescribed requirements, and is safe, efficacious and of good quality, the Authority is required to issue the applicant with a certificate of registration in respect of the relevant medicine. Regard must also be had to the General Regulations and the forms and guidelines issued and revised from time to time by the Authority.
In South Africa, these registration certificates are not publicly available documents.
As regards the renewal of registration certificates, strictly speaking, the Medicines Act provides that the registration of medicines is valid for a period of five years, however, practically speaking, the pharmaceutical industry does not attend to the five-yearly renewal of any medicine registrations.
In recent years, CAMs have been called up by the Authority and are now subject to registration in accordance with the provisions of the Medicines Act. As such, the manufacturers, distributors, importers and exporters of CAMs are equally required to be licensed in accordance with the Medicines Act.
Subject to certain exceptions, medical devices were previously not heavily regulated in South Africa. Prescriptive requirements for medical devices were not in force and advertisers and marketers of medical devices had few legislative and regulatory formalities to comply with.
As of December 2016, the local regulatory framework governing medical devices underwent a substantial legislative change, requiring, inter alia, the registration of medical devices, the licensing of manufacturers, wholesalers and distributors of medical devices and further providing guidelines regarding the advertising and labelling of medical devices.
The primary purpose of the Regulations Relating to Medical Devices and In Vitro Diagnostic Medical Devices (the Device Regulations) is to provide for the registration of medical and IVD devices, including matters related thereto.vi Regulatory incentives
There is no connection between the regulatory approval process for medicines and the patent and intellectual property protection regime in South Africa.
South Africa currently has a deposit-based patent filing system with no examination and opposition. Accordingly, and provided that the prescribed formal requirement for the lodging of a patent is complied with, such application will be granted.
The Cabinet of South Africa recently adopted and published a new intellectual property policy that, inter alia, addresses proposed reforms to the intellectual property regime in South Africa.
It is envisaged that government will leverage off of the flexibilities allowed in terms of the Trade-Related Aspects of Intellectual Property Rights rules of the World Trade Organization and for the purpose of promoting public health, local manufacturing, research and development, transfer of technology and socio-economic development.
This includes the introduction of a system of substantive search and examination (SSE) for patents to replace the current depository system in respect of certain fields of technology, with pharmaceuticals being identified as prime candidates. It is envisaged that SSE will benefit patent holders by granting rigorously assessed rights and ensuring that market exclusivity is only granted when appropriate. In addition, it is also envisaged that new patentability criteria will be adopted to address South Africa's public health and environmental concerns, as well as industrial policy objectives.vii Post-approval controls
Persons that have applied for the registration of medicine and persons that are holders of certificates of registration (HCRs) with regard to medicines are required to inform the Authority of new or existing quality, safety or efficacy concerns related to any medicine or scheduled substance, including but not limited to any adverse drug reactions (ADRs). In addition, such persons are required to maintain or have access to records of the reports and case reports made.
More generally, HCRs are required to have an appropriate pharmacovigilance system, which they must adequately maintain.
The Authority in its Post-marketing Reporting of Adverse Drug Reactions to Human Medicines in South Africa guideline sets out the framework that HCRs are required to follow in terms of reporting any ADRs. This guideline also addresses the management of safety data during post-registration and post-marketing clinical trials.
It is generally advisable that a suitably qualified pharmacovigilance officer be nominated by the responsible pharmacist.
Certificates of registration may be transferred from the existing HCRs to any other appropriately licensed person, subject to an application being made in the prescribed form and the same being granted by the Authority.viii Manufacturing controls
Guidelines are issued by the Authority from time to time, which relate to various matters including good manufacturing practices (GMP) or good distribution practices (GDP). All pharmaceutical manufacturers and wholesalers are required to comply with such guidelines.
The Department of Health further requires that premises licences be held by the relevant pharmaceutical manufacturer or wholesaler. Such a licence may be withdrawn in the event of any contravention of the provisions of the Medicines Act or the Pharmacy Act 53 of 1974 (the Pharmacy Act), or a failure to comply with GMP or GDP.
Manufacturers of medical devices must ensure that they have adequate quality management systems in place, with ISO 13485:2016 being the benchmark. The benefit of this is that manufacturers can decide whether or not they wish to have a quality management system for each of their sites or just one system that will apply to multiple sites.ix Advertising and promotion
The advertising to the public of medicines listed per Schedule 2 or above is prohibited in terms of the General Regulations.
In addition, Regulation 21 of the Device Regulations provides that only Class A or Class B medical devices may be advertised to the 'public or a lay person'. In terms of the Device Regulations, Class A refers to medical devices that are classified as 'low risk', and Class B refers to medical devices that are classified as 'low–moderate risk'.
Advertisement is defined in the Medicines Act as, inter alia, as any written, pictorial, visual or other descriptive matter or verbal statement or reference that is intended to promote the sale of a product.
Furthermore, the advertising and promotion of medicines and medical devices to healthcare professionals and the public is regulated in terms of the South African Code of Marketing Practice for Health Products (the Code), a voluntary marketing code that is intended to signify the industry's commitment to ensure that the marketing of health products is carried out in a responsible, ethical and professional manner.
The enforcement of the Code has been entrusted to a Marketing Code Authority and enforcement is generally based on the principle of self-regulation through the handling of complaints raised.x Distributors and wholesalers
Section 22C(6) of the Medicines Act provides that no manufacturer, wholesaler or distributor may manufacture, import, export, act as a wholesaler of or distribute, as the case may be, any medicine, scheduled substance or medical device, unless licensed.
In respect of a pharmaceutical manufacturer licence, this may include a licence to import or export medicines, or to act as a wholesaler of medicines.
Guidelines have been issued by the Authority, which are revised from time to time and relate to various matters including GMP and GDP. All pharmaceutical manufacturers and wholesalers are required to comply with such guidelines.
In addition, a pharmaceutical manufacturer or wholesaler must be licensed and recorded as a manufacturing or wholesale pharmacy, as the case may be, with the South African Pharmacy Council (the Pharmacy Council), and must further be recorded as a pharmacy owner.
Additional requirements of the Pharmacy Council include the appointment of a dedicated responsible pharmacist who is required to continually and personally supervise the operations of the relevant manufacturing or wholesale pharmacy.
The Department of Health further requires that premises licences be held by the relevant pharmaceutical manufacturer or wholesaler. Such a licence may be withdrawn in the event of any contravention of the provisions of the Medicines Act or the Pharmacy Act, or the failure to comply with GMP or GDP.
The Device Regulations provide, inter alia, for the following:
- the process for the application by a manufacturer, wholesaler or distributor of medical and IVD devices for a manufacturer, distributor or wholesaler licence. The Device Regulations go further to indicate the period of validity of a licence and provide for the renewal thereof; and
- details regarding the application process for the registration of medical and IVD devices as well as the classification thereof.
Notwithstanding the above, the Authority has not yet called up medical devices for registration; however, the Authority has initiated the licensing process for parties engaging in medical devices-related manufacturing, distribution and wholesale activities.
Applicants are required to appoint an 'authorised person', and the Device Regulations provide that such person needs to be 'suitably qualified' when it comes to the medical device or categories of medical devices held, imported or manufactured by the relevant applicant. If an applicant has multiple sites of manufacture and distribution, an application must be submitted per site, with an authorised representative appointed in respect of each site.xi Classification of products
There are four basic categories of medicines, and each category is further subdivided into a number of listed pharmacological classes.
The four categories are:
- Category A: medicines that are intended for use in humans and that are, without manipulation, ready for administration, including packaged preparations where only a vehicle is added to the effective medicine;
- Category B: medicines intended for use in humans and animals that cannot normally be administered without further manipulation;
- Category C: medicines intended for veterinary use that are, without further manipulation, ready for administration, including packaged preparations where only a vehicle is added to the effective medicine; and
- Category D: complementary medicines intended for use in humans and animals that are, without further manipulation, ready for administration, including packaged preparations where only a vehicle is added to the effective medicine.
In terms of the Medicines Act, substances are further classified in terms of a scheduling system from Schedule 0 through Schedule 8, the latter being the most highly controlled.xii Imports and exports
No person may import or export any Schedule 5, Schedule 6, Schedule 7 or Schedule 8 substance, unless a permit has been issued by Director-General of the Department of Health in the prescribed manner.xiii Controlled substances
Schedule 0 medicines may be sold to the public in an 'open shop'. This means that sales of such medicines are not restricted to pharmacies, whereas medicines of Schedule 1 and above may only be sold to the public in a pharmacy. Medicines of Schedule 3 and above require the prescription of a medical practitioner or another applicable healthcare professional.xiv Enforcement
The Medicines Act, the regulations thereto and the National Health Act set out their own list of offences and penalties, and include both monetary penalties and criminal offences. In addition the Authority has wide powers that include the authority to launch inspections, request documents and information, and revoke and suspend registrations and licences.