The need for global harmonisation of Regulation and Compliance requirements has seen the formation of, amongst others, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human use (ICH), which aims to bring together the regulatory authorities and pharmaceutical industry to discuss scientific and technical aspects of drug registration.
This Council has gradually evolved and expanded since its inception in 1990 to respond to increasing drug developments and evolving requirements in terms of the requirements for registration of drugs in different countries.
There have been many changes and updates within the South African Regulatory and Compliance framework to also include and provide more formal regulation of medical devices and In Vitro diagnostics (IVDs).
The manner in which these changes and updates impacts practice within the clinical research field is being reviewed.
Rules and Regulations in South Africa
In South Africa the Medicines and Related Substances Act (101 of 1965) and the Regulations under this Act, regulate the processes involved in Clinical Research, drug and medical devices, IVD development and ultimately the registration and/or licencing of products in the country.
Regulation 30 of the General regulations under the Medicines Act provides clear guidelines on how Clinical Trials must be applied for and managed for medicines. Similarly the requirements relating to the conduct of clinical trials and clinical investigations for medical devices and IVDs are set out in Regulation 16 of the Regulations relating to medical devices and In Vitro diagnostic medical devices (IVDs) under the Medicines Act.
In both instances an application must be made to the Authority on the prescribed form for authorisation of the conduct of such a clinical trial. Further requirements include that the application must be accompanied by the prescribed fee, a clinical trial protocol, the Principal Investigator’s brochure containing the relevant chemical, pharmaceutical, pre-clinical pharmacological and toxicological data and human or animal pharmacological data where applicable.
Equally important is the inclusion of details about the site where the clinical research will be conducted and the approval of that from the relevant health research ethics committee (which must be registered with the National Health Research Ethics Council in terms of the National Health Act 2003(61 of 2003), one of the many requirements to which such an application must adhere.
Every clinical trial must be conducted in accordance with guidelines for good clinical practice. There are separate guidelines published by the Department of Health that provide specific and detailed information in this regard namely, the “Guidelines for Good Practice in the Conduct of Clinical Trials with Human Participants in South Africa”.
Section 18A and 18B exemption – does it have any impact on how Clinical Trials are conducted?
One of the questions raised when dealing with the research, development and distribution of products, especially where it relates to medical devices and IVDs, is the exemption which was granted in terms of s18A and s18B of the Act which relate to sampling and bonusing of medical devices and IVDs for a period of one year from the date of publication in the Government Gazette on 29 December 2017.
Section 18A states:
“(1) No person shall supply any medicine, medical device or IVD according to a bonus system, rebate system or any other incentive scheme.
(2) Notwithstanding subsection (1), the Minister may prescribe acceptable and prohibited acts in relation to subsection (1) in consultation with the Pricing Committee referred to in Section 22G.”
Section 18B states:
“(1) No person shall sample any medicine, medical devices or IVD;
(2) Use of medicine, medical device or IVDs for exhibition or appraisal purposes shall be as prescribed;
(3) For the purposes of this section “sample” means the free supply of products, medical devices or IVDs by a device or IVDs establishment, manufacturer or wholesaler or its agent to a pharmacist, medical practitioner, dentist, veterinarian, practitioner, nurse or other person registered under the Health Professions Act, 1974 (Act No 56 of 1974), or any professional or person authorized to use the device.”
Medication, medical devices and IVDs in the testing phase are provided to patients who are participants in a clinical trial because they are already suffering from an illness or condition that requires an intervention, an intervention which may still be in clinical trial phase and not yet a registered product on the market. Desperate times often call for desperate measures.
Potential positive results, expressed or implied by either the Principal Investigator, the manufacturer of the product or any staff member whether assisting in conducting the clinical trial or not – is not the main reason a patient enrols as a participant in a clinical trial.
The hope from a patient’s perspective is that their symptoms may be alleviated by the use of the trial product. It could be argued that there is an automatic incentive present, though one created by the patient’s expectations and not by the manufacturer or the Principle Investigator in charge of the clinical trial.
A further predicament faced by many researchers in the past was that the sampling of medicines, medical devices and IVDs were prohibited in terms of s18B (1). The definition of sampling includes the free supply of products, medical devices or IVDs by, among others, the manufacturer or wholesaler, medical practitioner, pharmacist and nurses. This created some uncertainty within the clinical research environment because a constrictive interpretation of s18B(1) is that no medicine, medical device or IVD may be provided free of charge to any person; yet technically this is what occurs when a clinical trial is conducted.
The exemptions provided in the Government Gazette No 41362 have already seen positive outcomes in the research and development area of the clinical research industry. However, uncertainty exists regarding how the industry would function should the Registrar lift the exemption, given that many transactions have been concluded and actions taken on the basis of these exemptions.
These questions remain unanswered but will surely be tested at some point if the exemptions are lifted without any specific avenues for conduct, guidelines or procedures provided by the Regulatory Authority on how to manage the break in continuity in this regard. At this stage, there has been no indication from the Registrar of Medicines of a plan of action once the period of exemptions concludes.
In so far ethical review is concerned, the guidelines from the Department of Health on good clinical practice in the conduct of clinical trials require that a Principal Investigator conducting clinical research must follow fully the guidelines set out in each of the following:
- Declaration of Helsinki;
- ICH Guidelines for Good Clinical Practice;
- International Ethical Guidelines for Biomedical Research Involving Human subjects;
- Ethics in Health Research: Principles, Structures and Processes;
- and The Guidelines on Ethics for Medical research: HIV Preventive Vaccine Research.
The South African requirements include that all medical research involving human participants must undergo an independent ethical review. A Research Ethics Committee must consider a proposal for a study, taking into account the following list which includes but is not limited to:
- scientific relevance of the clinical study;
- suitability of the investigator(s) for the proposed study in terms of his/her availability,
- qualification, experience, supporting staff, and available facilities;
- risk-benefit analysis taking full cognisance of benefits and harms beyond the life of the study itself, particularly in relation to chronic life-threatening conditions;
- suitability of the study population, whether they constitute a vulnerable group, if so, whether the study is justified and whether sufficient measures to protect their interests are in place.
There are many different considerations which have been addressed through the various national and international requirements as set out in the guideline documents already discussed.
In South Africa Clinical Trial approval is provided on the following basis:
- Approval from the National Regulatory Authority;
- Approval from a Research Ethics Committee;
- Recording the trial information on the South African National Clinical Trials Register;
Research ethics committees have the authority to exclude trials exposing participants to substantial risks of serious harms. Thus, in the event that a participant exercises poor judgment, they are protected from research with unfavourable risk – this relates to benefit profiles.
When the research ethics committee reviews research proposals, they must focus on ensuring that the research is ethical and presents a favourable risk-benefits ratio.
Though the intent is good, and in the best interest of the clinical trial participants, the problem with so many different requirements in so many different jurisdictions, is that it creates an unnecessary burden on pharmaceutical and other manufacturing companies to comply with every regulatory and compliance requirement internationally. This creates less favourable circumstances for international companies to conduct their clinical trials in South Africa, for example.
Ultimately bringing their product into a new country and having it registered in order for it to be officially sold in the market becomes an almost impossible task.
Between the ethical and regulatory requirements to which applications for, and conducting of Clinical Trials must adhere, it is understandable that global harmonisation of requirements is sought.
South Africa requires adherence to the relevant international guidelines but despite this, there is too much red tape international companies are required to navigate in order to have their product reach the market. Certain exemptions have created a platform for companies to conduct their business more freely but this has not created a solution for the bigger problem.
Global harmonisation of regulatory and compliance requirements is not just a good idea, it is the ideal, the best practice by which we must measure ourselves. The South African Health Products Regulatory Authority has a golden opportunity to take part in and collaborate with those in the Life Sciences Industry, to ensure the South African voice is heard on an International platform. The ICH is the perfect place to start.