African Health Products Regulatory Authority Research Articles

What’s new for the clinician – summaries of recently published papers

To date, very few treatments have been demonstrated to reduce the burden of morbidity and mortality from COVID-19. Although corticosteroids have been proven to reduce mortality in severe disease, there has been little convincing evidence on interventions that may prevent disease, reduce hospitalizations, and reduce the numbers of people progressing to critical disease and death. Ivermectin is a well-known medicine that is approved as an antiparasitic by the World Health Organization and the US Food and Drug Administration. It is widely used in lowand middle-income countries to treat worm infections. Also used for the treatment of scabies and lice, it is one of the World Health Organization’s Essential Medicines.1 With total doses of ivermectin distributed apparently equalling one-third of the present world population,1 ivermectin at the usual doses (0.2–0.4 mg/kg) is considered extremely safe for use in humans.1 In addition to its antiparasiticactivity, it has been noted to have antiviral and anti-inflammatory properties, leading to an increasing list of therapeutic indications. South African authorities approved the use of a drug used to control parasites in humans and livestock to treat coronavirus patients. Additionally, in January 2021, the South African Health Products Regulatory Authority (SAHPRA) announced that ivermectin, would be allowedfor use on compassionate grounds in a controlled-access program. Ivermectin locally has been used for the prevention and/or management of Covid-19 infection. This has resulted in a huge black market trade of ivermectin in South Africa as many health professionals and others have taken to social media and other platforms to profile this drug as an effective treatment for the covid-19 viral infection. Roman and colleagues (2021)1 conducted a systematic review and meta-analysis to evaluate treatment effects of Ivermectin (IVM) on clinical outcomes and adverse events (AEs) in people with COVID-19.

South African Regulatory Authority: The Impact of Reliance on the Review Process Leading to Improved Patient Access.

Background: The aims of this study were to compare the overall regulatory review timelines achieved by the South African Health Products Regulatory Authority (SAHPRA) in 2020 to the timelines historically achieved by the Medicines Control Council (MCC). This study also aimed to evaluate the regulatory review processes and the good review practices that have been implemented by SAHPRA to support the assessment of new chemical entities and generic product applications for market authorization in the business-as-usual and backlog process streams. Methods: A questionnaire was completed and verified by SAHPRA to describe the structure of the organization, the resources available, the process for regulatory review of new chemical entities and generic products and the level of implementation of good review practices and regulatory decision-making practices for market authorization. Data were collected and analyzed on the overall approval timelines for new chemical entities and generic products registered by SAHPRA in 2020 in the business-as-usual and backlog process streams. Results: A full, independent scientific review was conducted for all new chemical entities and generic product applications in the business-as-usual stream. Facilitated regulatory pathways were introduced for the review of new chemical entities and generic products in the backlog stream. As a result, the timelines for approval of applications in the backlog stream were 68% quicker for both new chemical entities and generics, using facilitated regulatory pathways, such as abridged and verification review models. Conclusion: The comparisons made through this study provided insight into the improvements that have been made through the establishment of SAHPRA and the transition in 2018 from the MCC. The re-engineered processes that have been developed and implemented by SAHPRA to address the backlog in the review of the applications for market authorization have demonstrated a decrease in the overall median approval times. The expansion of these processes into the routine review of medical products will contribute to the enhanced regulatory performance of SAHPRA and patients’ access to new medicines.

SAHPRA - Relevance of the New South African Health Products Regulatory Authority and Opportunities Ahead

Regulatory environments are constantly evolving, and South Africa has witnessed some significant developments in the recent past. Operational launch of the South African Health Products Regulatory Authority (SAHPRA) as new healthcare products regulator marks a key milestone in the establishment of international standards in regulatory practices. Both the Medicines Control Council (MCC) and the Directorate of Radiation Control (DRC) were replaced by SAHPRA to bring control of medicines, medical devices, in vitro diagnostic tests and devices, and radiation emitting products under one regulatory body. The new agency was instituted under schedule 3A of Public Finance Management Act as public entity, thereby enabling it to retain the revenue generated. The change has evidently impacted the regulatory practices positively; however, the challenges inherited by regulators and those regulated are enormous. SAHPRA needs to confront the challenges and make the most out of the opportunities ahead. This study aims to focus on understanding the new agency, its evolution over time, objectives set forth, organizational and operational construct, responsibilities, accomplishments so far, outstanding challenges, opportunities ahead, and the collaborative efforts that can support its operation. SAHPRA has had noteworthy achievements as a healthcare products regulator. By making most use of collaboration efforts SAHPRA is all set to work through the challenges and gain from opportunities. https://doi.org/10.21423/jrs-v09i2dureja

Ivermectin and the rule of law

The ivermectin saga has taken on a new dimension: respect for the rule of law by the state. The rule of law is important, as it is a cornerstone of our democratic Constitutional order. The South African Health Products Regulatory Authority (SAHPRA) has a statutory mandate to regulate medicines and related substances, but it also has a constitutional duty to obey the law. This duty includes obeying court orders. However, SAHPRA appears to have contravened the consent order handed down by the Pretoria High Court on 2 February 2021, and therefore undermined the rule of law. This situation is untenable in our democratic Constitutional order.

A Proposed Regulatory Review Model to Support the South African Health Products Regulatory Authority to Become a More Efficient and Effective Agency.

Background: National regulatory agencies of various sizes and maturity levels, including the South African Health Products Regulatory Authority (SAHPRA), have had to revise systems and re-engineer processes in order to adapt to the new regulatory environment and increase the effectiveness of regulatory operations. This study aimed to develop a new regulatory review model for improved regulatory performance, underpinned by the parameters of the World Health Organization Global Benchmarking Tool (WHO GBT) that support strengthening of regulatory systems. Methods: A new enhanced model for regulatory review, was developed based on the key recommendations from 6 studies, previously conducted by the authors, that were identified as fundamental elements in enhancing regulatory performance. The elements selected to define the new regulatory review model were endorsed through the integration of the parameters of the WHO GBT that, when embedded within regulatory systems, support enhanced regulatory performance. Results: Opportunities for improvement in regulatory performance were identified and include quality measures; monitoring and evaluating review times; a risk-based evaluation; transparency and communication; and training and education. An improved model for the South African regulatory review and benefit-risk (BR) assessment supported by quality decision-making was proposed as well as recommendations for the application of risk-stratification strategies, strengthening of reliance networks, reinforcing good regulatory practices (GRPs) and enhancing transparency. Conclusion: If implemented the proposed improved regulatory model may pave the way towards more efficient and transparent, streamlined review processes, coupled with increased consistency, evidence-based decision-making practices, reduced timelines and improved patients’ access to new medicines in South Africa.

Assessing the safety and pharmacokinetics of the anti-HIV monoclonal antibody CAP256V2LS alone and in combination with VRC07-523LS and PGT121 in South African women: study protocol for the first-in-human CAPRISA 012B phase I clinical trial

IntroductionNew HIV prevention strategies are urgently required. The discovery of broadly neutralising antibodies (bNAbs) has provided the opportunity to evaluate passive immunisation as a potential prevention strategy and facilitate vaccine...

‘It’s like making your own alcohol at home’: Factors influencing adolescent use of over-thecounter cough syrup

Background. Adolescents are increasingly experimenting with new ‘craze drugs’, including over-the-counter cough medicine (OTCCM). However, there is limited empirical evidence regarding South African (SA) adolescents’ use of codeine-containing medicines, especially OTCCMs. Objective. To describe SA adolescents’ views of OTCCM misuse, and the factors that may promote its use. Methods. The research adopted an exploratory qualitative design. Focus group discussions ( N =24) were conducted with 144 learners between 14 and 17 years old in two township communities in SA. Data were analysed thematically supported by Atlas.ti. Results. Three core themes emerged from the analysis, namely knowledge of OTCCM use; factors that influence OTCCM use; and effects of OTCCM use. Participants reported that young people use OTCCM recreationally. Four main factors were noted to influence OTCCM misuse in their communities, namely accessibility, affordability, social influences and the clandestine appeal of cough medicine. Adolescents also said that OTCCM had similar euphoric effects to alcohol or marijuana, but could not readily describe any negative impact. Conclusion. This exploratory study with adolescent participants provides contextualised empirical evidence about OTCCM. The findings call for the South African Health Products Regulatory Authority (SAHPRA) to promptly consider pending regulations on OTC codeinecontaining medication and demands increased awareness of codeine misuse in communities.

Testing the regulatory framework in South Africa \u2013 a single-blind randomized pilot trial of commercial probiotic supplementation to standard therapy in women with bacterial vaginosis

BackgroundBacterial vaginosis (BV) increases HIV risk and adverse reproductive outcomes. Standard-of-care (SOC) for BV are antibiotics; however, cure rates are low. Probiotics for vaginal health may be useful in improving cure and recurrence although the regulatory framework governing probiotics and the conduct of randomized clinical trials to evaluate these has not been established in South Africa. We performed an exploratory single-blind trial evaluating a commercial oral-vaginal-combination probiotic as adjunct to SOC for BV treatment.MethodsWomen with symptomatic vaginal discharge were screened for BV and common sexually transmitted infections (STIs). BV+ (Nugent 7–10) but STI- women were randomized to vaginal metronidazole alone (n = 12) or to metronidazole followed by a commercial oral/vaginal probiotic (n = 18). The primary qualitative outcome was to test the regulatory landscape for conducting randomized probiotic trials in South Africa; and acceptability of vaginal application by women. BV cure at 1 month (Nugent≤3) was the primary quantitative endpoint. Secondary quantitative endpoints were BV recurrence, symptoms, vaginal microbiota and genital cytokine changes over 5 months post-treatment.ResultsThe South African Health Products Regulatory Authority (SAHPRA) reviewed and approved this trial. As probiotics continue to be regulated as health supplements in South Africa, SAHPRA required a notification application for this trial. Acceptability and adherence to the oral and vaginal application of the probiotic were high, although women reported a preference for oral capsules. 44.8% of women cleared BV one-month post-treatment, and no significant differences in BV cure (RR = 0.52, 95% CI = 0.24–1.16), recurrence, vaginal pH, symptoms, microbiota or vaginal IL-1α concentrations were found between SOC and intervention groups in this pilot study with an over-the-counter product.ConclusionNavigation of the SAHPRA registration process for evaluating a commercial probiotic in a randomised trial laid the foundation for planned larger trials of improved probiotic products for vaginal health in South Africa. Although adherence to the vaginally delivered probiotic was high, women preferred oral application and we recommend that improvements in the content and method of application for future probiotics for vaginal health should be considered.Trial registrationThis trial was registered on 17 October 2017 with the South African National Clinical Trial Register (http://www.sanctr.gov.za/; BV-trial1; DOH-27-1117-5579).

Increased Bactericidal Activity But Dose-Limiting Tolerability at 50 mg/kg Rifampicin

Background: Accumulating data indicate that higher rifampicin doses may be more effective and shorten tuberculosis treatment duration. This study evaluated the safety, tolerability, pharmacokinetics, and 14-day early bactericidal activity (EBA) of increasing doses of rifampicin. Methods: We performed a dose-escalation study in treatment-naive adult smear-positive tuberculosis patients. Patients received, in consecutive cohorts, 40 or 50mg/kg rifampicin once daily in monotherapy (day 1-7), supplemented with standard doses of isoniazid, pyrazinamide and ethambutol between day 8-14. Safety, tolerability, pharmacokinetics, and EBA were assessed. Findings: In the 40mg/kg cohort (n=15), 13 patients experienced adverse events (AEs) during monotherapy (n=36), resulting in one treatment discontinuation in the combination phase. In the 50mg/kg group (n=17), all patients experienced AEs during monotherapy. There were more AEs in total (n=93) compared to 40mg/kg, and eleven patients withdrew or stopped study medication. AEs were mostly mild or moderate (≤grade 3) and tolerability related, i.e. gastrointestinal disorders, pruritis, hyperbilirubinemia and jaundice. A more than proportional increase in rifampicin exposure with dose was observed, in line with previous cohorts. EBA increased considerably with dose; with the highest seen in the 50mg/kg cohort. Interpretation: Our research concludes a journey that started in the 1960s. Rifampicin up to 40mg/kg was well tolerated. Although associated with an increased bactericidal effect, the tolerability of a 50mg/kg dose was poor. Rifampicin at 40mg/kg appears to be the optimal dose for evaluation in a phase IIB/C treatment shortening trial. Trial Registration: Here we report the results of the final cohorts of the PanACEA HIGHRIF1 trial (clinicaltrials.gov NCT01392911). Funding Statement: This publication was produced by PanACEA, which is part of the European and Developing Countries Clinical Trials Partnership (EDCTP) 1 programme [project code IP.2007.32011.012 (HIGHRIF)] and the EDCTP2 programme supported by the European Union (grant number TRIA2015-1102-PanACEA). Declaration of Interests: We declare no competing interests. Ethics Approval Statement: The study protocol was approved by the applicable ethical review boards and by the South African Health Products Regulatory Authority and was conducted according to international and South African Good Clinical Practice guidelines.

Assessing the safety and pharmacokinetics of the monoclonal antibodies, VRC07-523LS and PGT121 in HIV negative women in South Africa: study protocol for the CAPRISA 012A randomised controlled phase I trial

IntroductionDespite extensive prevention campaigns and scale-up of antiretroviral therapy, HIV incidence among young women in southern Africa remains high. While the development of an efficacious vaccine remains a challenge, the...

The South African Medicines Control Council: Comparison of Its Registration Process With Australia, Canada, Singapore, and Switzerland.

Introduction: Comparisons between regulatory authorities of similar size and regulatory characteristics facilitate value-added benchmarking and provide insight into regulatory performance. Such comparisons highlight areas for improvement as authorities move toward achieving their regulatory goals and stakeholders’ demands. The aims of this study were to compare the registration process and the regulatory review model of the South African Medicines Control Council (MCC) to that of four other similar-sized regulatory authorities and to identify areas for improvement that may inform recommendations to the South African Health Products Regulatory Authority (SAHPRA) as it looks to re-engineer and enhance the registration process in South Africa.Methods: A questionnaire describing the organisational structure, the registration process, good review and decision-making practices of the MCC was completed by the author (AK) for the purpose of this study and validated by the Registrar of the MCC. Similar questionnaires were also completed and validated by Australia’s Therapeutic Goods Administration (TGA), Canada’s Health Canada, Singapore’s Health Science Authority (HSA) and Switzerland’s Swissmedic.Results: A comparison of the MCC regulatory process with the four comparative agencies indicated that they all have similar requirements and employ a full-review model although the timelines for the MCC were considerably longer. However, similar quality measures were implemented by all authorities as part of their good review practices (GRevP) including prioritising transparency, communication, continuous improvement initiatives and training.Conclusion: Comparisons made through this study provided insight into the areas of the MCC registration process that may be improved and have informed recommendations to SAHPRA including the implementation of facilitated regulatory pathways, definition of targets for key milestones in regulatory review and formal implementation and monitoring of GRevP. In order to build quality into the review process the application of a standardised template for the clinical assessment of medicines such as the Universal Methodology for Benefit-Risk Assessment (UMBRA) could be considered as well as enhancing transparency and communication through the application of an electronic management system and the development of publicly available summaries for the basis of approval.

The South African Regulatory System: Past, Present, and Future.

The drive for improved regulatory systems and the establishment of a more effective regulatory framework in South Africa has been evident for the past two decades but despite political intentions and legislative revisions success has been limited to date. Efforts to address the increasing volume of applications that have been received have to date failed and resources have been stretched to capacity resulting in the development of a significant backlog and extended timelines for product registration. The promulgation of the recently amended Medicines and Related Substance Act of 1965 triggered the establishment of the South African Health Products Regulatory Authority (SAHPRA) as a separate juristic person outside of the National Department of Health to replace the former medicine regulatory authority the Medicines Control Council (MCC). The aim of this review is to provide the historical context supporting the new regulatory environment in South Africa and the transition from the MCC to SAHPRA. Key recommendations to SAHPRA to ensure the full potential of the new regulatory environment in South Africa include: establishing a quality management system to safeguard accountability, consistency and transparency and to streamline the implementation of good review practices including quality decision-making practices and benefit-risk assessment; the measurement and monitoring of regulatory performance, targets for overall approval time and key review milestones to instill a culture of accurate metrics collection and measurement of key performance indicators and their continuous improvement and the employment of a risk-based approach to the evaluation of medical products and codify the use of facilitated regulatory pathways in policy and culture. The application of a risk-based approach to regulatory review commensurate with a product’s risk to patients will facilitate the application of increased resources for pharmacovigilance activities and to support the reliance and recognition of reference agencies.

Understanding the Amino Acid Profile of Whey Protein Products

BACKGROUND: The South African dietary supplement market will undergo a period of transition within the next few years due to the establishment of the South African Health Products Regulatory Authority (SAHPRA), which has superseded the former Medicines Control Council (MCC). While regulatory steps are yet to be fully outlined, products such as whey protein, regarded as food, will be governed by the Department of Health R429 draft Regulations Relating to the Labelling and Advertising of Foods. The guideline provides for the minimum value of essential amino acids (plus cysteine and tyrosine) per gram of protein that products claiming to contain protein will be required to comply with. Determining the compliance levels of whey protein products currently available will assist in establishing the readiness of the dietary supplement industry for regulation, and provide an indication of the overall state of the industry.OBJECTIVES: To determine the amino acid profile of whey protein powder and compare analysed content to manufacturer stated content.To compare analysed amino acid content to the Department of Health R429 draft Regulations Relating to the Labelling and Advertising of Food template amino acid profile.METHOD: 15 of the best-selling whey protein products available in South Africa were selected for amino acid analysis. Tested amino acid content were compared to the label stated claim and the amino acid reference pattern, as stated in the Department of Health R429 draft Regulations Relating to the Labelling and Advertising of Foods.RESULTS: Sixty percent (60%) of products tested were non-compliant with the Department of Health R429 draft Regulations Relating to the Labelling and Advertising of Foods. Of the 15 products tested, 11 were manufactured in South Africa, with 8 being non-compliant to the guideline amino acid profile. Considerable variance was noted in the manufacturer stated and the tested amino acid content (ranging from 16–48% variance).CONCLUSION: Many of the whey protein products available in South Africa are not compliant to proposed industry guidelines. The considerable variance noted highlights the need for greater oversight of the industry with clearly defined regulatory procedures.

Plasma fractionation in South Africa: challenges and successes in meeting international standards

Africa represents a challenge to the provision of plasma-derived medicinal products (PDMPs) as there are many competing health priorities on a continent with limited investment and resources to support some of the poorest nations. To compound this, the availability of suitable plasma, although improving, severely limits better access to PDMP for patients in the region. The National Bioproducts Institute NPC (NBI), as a fractionator in South Africa, illustrates a model of local fractionation which successfully addresses some of the dilemmas faced by lower resourced countries in the broader African context. NBI is a relatively small fractionator in the South African pharmaceutical manufacturing landscape, which is characterised by rigorous local and international regulatory requirements, a volatile currency and restrictive pharmaceutical pricing practices. Further, NBI is confronted by a constantly evolving regulatory and operating environment, a paucity of active raw materials, dynamic market trends and variable patient demand for plasma derivatives, as diagnosis of many of the clinical conditions for which plasma derivatives are indicated, improves. Despite these challenges, NBI remains a sustainable and viable local fractionator, positioned to realise its strategic intent of providing accessible, affordable and a comprehensive range of essential PDMPs to patients in South Africa and the Southern African Development Community region. A key to NBI’s success is the strategic partnerships with the South African Blood Transfusion Services (BTS) and other industry associations, as well as a good working relationship with the local regulatory authority, the South African Health Products Regulatory Authority (SAHPRA).

The off-label use of medication in South Africa: What about some information for medical practitioners?

The Medicines and Related Substances Act (the Act) provides for the registration of medicine by the Medicines Control Council (MCC). In terms of the Medicines and Related Substances Amendment Bill, signed but not yet proclaimed, the MCC will shortly be replaced by the South African Health Products Regulatory Authority (SAPHRA). Despite major changes in the administrative structure, SAPHRA will probably have the same functions as the MCC. Section 14 of the Act forbids the sale of unregistered medicine.

Exorcising the Ghosts of Dr. No's War on Science: Exploring What the Constitution Means for the Institutions that Regulate Medicines

Since the Constitution of the Republic of South Africa, 1996 came into effect, legal action on a range of socio-economic rights - in particular the right to have access to health care services - has demonstrated the significant value of express constitutional recognition. Collectively, the cases highlight the link that often exists between successful rights-based legal action and civil society organisation, mobilisation and advocacy. Importantly, they show that the law - particularly insofar as it relates to positive claims on the state - is ordinarily a weak tool when used on its own, but often significantly more powerful when combined with activism.But these cases also raise deeper systemic questions about the health system. Collectively, they show that effective regulation and reasonable implementation of policies and programmes - as well as the ability of the state to meet its constitutional mandate - relies on the proper functioning of a number of independent regulatory and oversight institutions. Until recently, however, health rights litigation had largely overlooked these important concerns. To date, South African jurisprudence has yet to consider the nature and extent to which the Constitution imposes obligations on the state in respect of such institutions.With a singular focus on the regulation of medicines, this paper seeks to start to address this deficit. Cognisant of the broader legal and political context within which medicines have been regulated in South Africa over the past decade, it begins by exploring recent legislative moves to replace the Medicines Control Council (MCC). By considering proposals for the MCC's successor - the South African Health Products Regulatory Authority (the Authority) - as set out in the recently adopted Medicines and Related Substances Amendment Bill [B 44D-2008] (the Bill), this paper seeks to contextualise concerns regarding the Authority's structure and mandate.Thereafter, this paper considers the state's positive obligations in respect of regulatory institutions in general and drug regulatory authorities (DRAs) in particular. In so doing, it focuses on a wide range of legal developments in South Africa, including jurisprudence on socio-economic rights and other superior court decisions that consider constraints on the exercise of public power - openness, accountability, transparency, the delegation of subordinate legislative authority and the grant of discretionary powers. In particular, this paper considers the impact of the Constitution on certain aspects of the structure, mandate and operations of a DRA such as the Authority.This paper concludes by identifying ways in which new regulations to the Medicines Act - as amended by the Bill - could address outstanding concerns relating to the Authority's ability to discharge its functions effectively, efficiently and in accordance with the Constitution. Simply put, this paper ends by considering how best to address many - if not most - of the deficiencies in the Bill by way of the regulation drafting process. In so doing, it implicitly recognises that further opportunities for amending the Medicines Act - whether by way of law reform or litigation - are unlikely to arise in the short to medium term.