Health Products Regulatory Authority Research Articles

Common deficiencies found in generic Finished Pharmaceutical Product (FPP) applications submitted for registration to the South African Health Products Regulatory Authority (SAHPRA)

BackgroundThe aim of the study was to investigate the common deficiencies observed in the Finished Pharmaceutical Product (FPP) section of generic product applications submitted to SAHPRA. The study was conducted retrospectively over a 7-year period (2011–2017) for products that were finalised by the Pharmaceutical and Analytical pre-registration Unit.MethodsThere were 3148 finalised products in 2011–2017, 667 of which were sterile while 2089 were non-sterile. In order to attain a representative sample for the study, statistical sampling was conducted. Sample size was obtained using the statistical tables found in literature and confirmed by a sample size calculation with a 95% confidence level. The selection of the products was according to the therapeutic category using the multi-stage sampling method called stratified-systematic sampling. This resulted in the selection of 325 applications for non-sterile products and 244 applications for sterile products. Subsequently, all the deficiencies were collected and categorised according to Common Technical Document (CTD) subsections of the FPP section (3.2.P).ResultsA total of 3253 deficiencies were collected from 325 non-sterile applications while 2742 deficiencies were collected from 244 sterile applications. The most common deficiencies in the FPP section for non-sterile products were on the following sections: Specifications (15%), Description and Composition (14%), Description of the Manufacturing Process (13%), Stability Data (7.6%) and the Container Closure System (7.3%). The deficiencies applicable to the sterile products were quantified and the subsection, Validation and/or Evaluation (18%) has the most deficiencies. Comparison of the deficiencies with those reported by other agencies such as the USFDA, EMA, TFDA and WHOPQTm are discussed with similarities outlined.ConclusionsThe overall top five most common deficiencies observed by SAHPRA were extensively discussed for the generic products. The findings provide an overview on the submissions and regulatory considerations for generic applications in South Africa, which is useful for FPP manufacturers in the compilation of their dossiers and will assist in accelerating the registration process.

CAPRISA 018: a phase I/II clinical trial study protocol to assess the safety, acceptability, tolerability and pharmacokinetics of a sustained-release tenofovir alafenamide subdermal implant for HIV prevention in women

IntroductionYoung African women bear a disproportionately high risk for HIV acquisition. HIV technologies that empower women to protect themselves are needed. Safe, potent antiretroviral agents such as tenofovir alafenamide (TAF),...

Dapivirine Vaginal Ring for HIV Prevention in Women in South Africa

Young women remain disproportionately affected by the HIV epidemic in South Africa. Clinical trials have shown that the dapivirine vaginal ring (DVR) is safe and effective at reducing HIV infection in women. In March 2022, the South African Health Products Regulatory Authority approved the use of the DVR in women aged 18 years and older who are unable or unwilling to use oral pre-exposure prophylaxis, as an additional choice for preventing HIV in women at substantial risk. Modelling studies have suggested that the DVR could have a substantial impact if prioritized for women at substantial risk of HIV or women aged 22–29 years. The licensing of the DVR in South Africa is a milestone event that brings the first long-acting and woman-controlled HIV prevention method another step closer to reaching the people who need it. As South Africa prepares its introduction, it is critical to examine the unmet need for HIV prevention and to review the clinical trial data that led to the DVR's approval.

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.

An initial evaluation of the safety of a disposable oscillating positive expiratory pressure device in patients with chronic obstructive pulmonary disease: a short-term pilot study

BackgroundHandheld oscillating positive expiratory pressure (OPEP) devices have been a mainstay of treatment for patients with hypersecretory conditions such as cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) since the 1970s. Current devices are reusable and require regular cleaning and disinfection to prevent harbouring potentially pathogenic organisms. Adherence to cleaning regimens for respiratory devices is often poor and in response to this, a prototype disposable OPEP device—the ‘UL-OPEP’ (University of Limerick—Oscillating Positive Expiratory Pressure device)—was developed to mitigate the risk of contamination by pathogens. The device was previously evaluated successfully in a group of paediatric CF patients. The aim of the current study was to initially evaluate the safety of the prototype in patients with COPD over a period of 1 month to ensure no adverse events, negative impacts on lung function, exercise tolerance, or quality of life. Data on user experience of the device were also collected during post-study follow-up.MethodsA sample of 50 volunteer participants were recruited from pulmonary rehabilitation clinics within the local hospital network. The patients were clinically stable, productive, and not current or previous users of OPEP devices. Participants were invited to use a prototype disposable OPEP device daily for a period of 1 month. Pre- and post-study lung function was assessed with standard spirometry, and exercise tolerance with the 6-min-walk-test (6MWT). Quality of life was assessed using the St. George’s Respiratory Questionnaire (SGRQ), and user experience of the prototype device evaluated using a post-study questionnaire.Results24 Participants completed the study: 9 were female. Overall median age was 67.5 years, range 53–85 years. Lung function, 6-min walk test, and SGRQ scores showed no significant change post-study. User feedback was positive overall.ConclusionsThe results indicate that the UL-OPEP is safe to use in patients with COPD. No adverse events were recorded during the study or in the follow-up period of 2 weeks. The device did not negatively impact patients’ lung function, exercise tolerance, or quality of life during short term use (1 month), and usability feedback received was generally positive. Larger, longer duration studies will be required to evaluate efficacy.Registration The study was approved as a Clinical Investigation by the Irish Health Products Regulatory Authority (CRN-2209025-CI0085).

The Wavelia Microwave Breast Imaging system-tumour discriminating features and their clinical usefulness.

Objective:The Wavelia Microwave Breast Imaging (MBI) system, based on non-ionising imaging technology, has demonstrated exciting potential in the detection and localisation of breast pathology in symptomatic patients. In this study, the ability of the system to accurately estimate the size and likelihood of malignancy of breast lesions is detailed, and its clinical usefulness determined.Methods:Institutional review board and Health Products Regulatory Authority (HPRA) approval were obtained. Patients were recruited from the symptomatic unit to three groups; breast cancer (Group-1), unaspirated cysts (Group-2) and biopsied benign lesions (Group-3). MBI, radiological and histopathological findings were reviewed. MBI size estimations were compared with the sizes determined by conventional imaging and histopathology. A Quadratic Discriminant Analysis (QDA) classifier was trained in a 3D feature space to discriminate malignant from benign lesions. An independent review was performed by two independent breast radiologists.Results:24 patients (11 Group-1, 8 Group-2 and 5 Group-3) underwent MBI. The Wavelia system was more accurate than conventional imaging in size estimation of breast cancers. The QDA accurately separated benign from malignant breast lesions in 88.5% of cases. The addition of MBI and the Wavelia malignancy risk calculation was deemed useful by the two radiologists in 70.6% of cases.Conclusion:The results from this MBI investigation demonstrate the potential of this novel system in estimating size and malignancy risk of breast lesions. This system holds significant promise as a potential non-invasive, comfortable, and harmless adjunct for breast cancer diagnosis. Further larger studies are under preparation to validate the findings of this study.Advances in knowledge:This study details the potential of the Wavelia MBI system in delineating size and malignancy risk of benign and malignant breast lesions in a symptomatic cohort. The usefulness of the Wavelia system is assessed in the clinical setting.

SURAMIN INTRAVENOUS INFUSION FOR TREATING BOYS WITH AUTISM SPECTRUM DISORDER: RESULTS OF A 14-WEEK, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, MULTIDOSE, PHASE 2 STUDY

Objectives: The objective of this presentation is to test the efficacy and safety of 2 doses of suramin vs placebo in children aged 4 to 17 years with autism spectrum disorder (ASD). The hypotheses are that at least 1 of 2 suramin doses would show improvement in the Aberrant Behavior Checklist (ABC) Core score and that treatment would be safe and tolerable. Methods: Fifty-two boys were enrolled in 3 treatment arms: 10 mg/kg and 20 mg/kg, and placebo dosed at baseline, at weeks 4 and 8. Subjects were diagnosed by DSM-5 criteria and severity measured by the Autism Diagnostic Observation Schedule. The main efficacy analyses were ABC Core (subscales 2, 3, and 5) and Clinical Global Impression–Improvement (CGI-I) scale. Question 1 was assessed using intent-to-treat sample change scores from baseline to endpoint using ANOVA. Although the study was not designed for formal statistical comparison, ABC Core and CGI-I were tested at a family-wise Type I level of 0.05 using Dunnett’s p value for multiple comparisons. The study was approved by the South Africa Health Products Regulatory Authority and each site’s IRB. Results: The study was conducted at 6 sites in South Africa. The sample was multiracial with a mean age of approximately 8 years and a range of 4 to 15 years. There was a wide variability in the severity of ASD symptoms at baseline. Forty-four subjects completed the study, and there were 8 early withdrawals (COVID-19: 5;serious adverse event [SAE]: 1;other reason: 2). The 10 mg arm showed a sustained benefit across time points. The ABC Core modeling mean ± standard error (SE) of 10 mg showed a greater numeric improvement (–12.5 ± 3.18) vs placebo (–8.9 ± 2.86) (nonsignificant) at Week 14. The 20 mg arm did not show improvement vs placebo at Week 14. In exploratory analyses, the 10 mg arm showed greater differences from placebo in ABC Core in younger and less severe subjects. CGI-I modeled mean ± SE changes from baseline were 2.8 ± 0.30 (p = 0.016) in the 10 mg arm and 2.0 ± 0.28 (p = 0.65) in the 20 mg arm vs 1.7 ± 0.27 in the placebo. Suramin was generally safe and well tolerated over 14 weeks. There was 1 SAE, status epilepticus, in a subject (20-mg arm) with multiple risk factors for seizure;it resolved without sequelae. Conclusions: This dose-ranging proof-of-concept study showed some positive results from a treatment with a novel mechanism of action. Limitations include the small sample size and exploratory analyses that require confirmation in a larger study. Suramin was safe and tolerable over 14 weeks.

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.

A Validated and Licensed Method of Bone Marrow Aspirate Procurement to Support Advanced Therapy Investigational Medicinal Product (ATIMP) Manufacture

The Blood & Tissue Establishment (BTE) of Galway University Hospitals supplies sterile bone marrow (BM) aspirate to European cellular manufacturing facilities as a starting material in ATIMP manufacture. We have developed a validated, sterile bone marrow procurement method in accordance with the European Union Tissue & Cells Directive (EUTCD) and Good Manufacturing Practice (GMP). The BTE achieved the requisite procurement licence, from the Irish competent authority, the Health Products Regulatory Authority (HPRA).Under the BTE Quality Management System all standard operating procedures and forms are document controlled, all consumable items are batch accepted, all staff involved undergo training and competency assessment (including adequate sanitisation of the iliac crest), and all issues are recorded and reported appropriately to the HPRA.The prospective donor must first undergo a two part ‘donor assessment’ procedure which evaluates the donor's ‘fitness’ to undergo the procedure, while also having due regard for any potential recipient.Part One of the assessment process requires that the entire procedure is explained by a trained clinician / nurse; a patient information leaflet is provided and written consent obtained. A full blood count, coagulation screen, glucose test, chemistry screen, blood group and virology screen is performed. The virology screen must, at minimum, include the viruses listed by the EUTCD and the donation must take place within 30 days of sample collection. The patient will then undergo a ‘lifestyle questionnaire’ to assess donor medical, travel, sexual and other risk history. Guidance for allowing the donation to proceed will depend on a number of factors, including, whether it is an allogeneic or autologous donation. Consideration is given to the ‘Bone Marrow and Peripheral Blood Stem Cell Donor Selection Guidelines for Unrelated Donors’ of the ‘Guidelines for the Blood Transfusion Services in the United Kingdom’. HPRA and European Centre for Disease Prevention and Control alerts are also incorporated into selection criteria.The Responsible Person (RP) of the BTE (also a Consultant Haematologist) must review the answers to the questionnaire, together with the blood test results and assess whether the donor is fit to proceed to aspiration.Part Two of the assessment process takes place immediately prior to the scheduled aspiration. The donor will repeat the lifestyle questionnaire once more and the answers will be reviewed and compared with the previous questionnaire. The Consultant Haematologist will carry out a clinical examination and assessment of the donor. Upon completion, final donor eligibility is signed off and the aspiration can proceed. The procedure takes place in an operating theatre by a scrubbed Consultant Haematologist. A sterile field is created around the aspiration site. The aspiration site is cleansed with Chlorhexadine. Local anaesthetic (lidocaine 2%) is administered. 11 Gauge BM needles are used to puncture. Syringes are flushed with heparin sodium flushing solution. The flushed syringes are used to withdraw the BM, handed to a sterile assistant and transferred into 10ml lithium heparin vacutainers. The volume of 30ml of BM is aspirated from the iliac crest of both healthy donors (allogeneic) and patients (autologous) enrolled in clinical trials.These vacutainers are capped and inverted several times to prevent clotting, labelled and packaged for transport.The puncture site is dressed, donor vitals are observed and noted post procedure and the donor may be discharged after 2 hours.BM is transported to the manufacturing facility at monitored ambient temperature. Within the Grade A controlled environment, the BM is pooled and 1ml is used to inoculate one aerobic and one anaerobic blood culture bottle (validated for 0.5ml in each, incubated for 14 days, automated detection system).As of July 2017, we have performed 24 collections, 11 of which are allogeneic donations from healthy volunteers. The average white cell count in the aspirate from healthy donors is 43.1 x 106/ml. The sterility is satisfactory, with only one instance of contamination over the 24 collections, where, on the final day of incubation (day 14), we detected propionibacterium spp, a notoriously slow-growing commensal skin flora.Our regulatory approved protocol provides a steady supply of GMP grade bone marrow aspirates for the purpose of clinical trials. DisclosuresNo relevant conflicts of interest to declare.

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

A short-term evaluation of a prototype disposable Oscillating Positive Expiratory Pressure (OPEP) device in a cohort of children with cystic fibrosis

BackgroundOscillating Positive Expiratory Pressure (OPEP) devices are important adjuncts to airway clearance therapy in patients with cystic fibrosis (CF). Current devices are typically reusable and require daily, or often more frequent, cleaning to prevent risk of infection by acting as reservoirs of potentially pathogenic organisms. In response, a daily disposable OPEP device, the UL-OPEP, was developed to mitigate the risk of contamination and eliminate the burdensome need for cleaning devices.MethodsA convenience sample of 36 participants, all current OPEP device users, was recruited from a paediatric CF service. For one month, participants replaced their current OPEP device with a novel daily disposable device. Assessment included pre- and post-intervention lung function by spirometry, as well as Lung Clearance Index. Quality of life was assessed using the Cystic Fibrosis Questionnaire – Revised, while user experience was evaluated with a post-study survey.Results31 participants completed the study: 18 males; median age 10 years, range 4–16 years. Lung function (mean difference ± SD, %FEV1 = 1.69 ± 11.93; %FVC = 0.58 ± 10.04; FEV1: FVC = 0.01 ± 0.09), LCI (mean difference ± SD, 0.08 ± 1.13), six-minute walk test, and CFQ-R were unchanged post-intervention. Participant-reported experiences of the device were predominantly positive.ConclusionsThe disposable OPEP device maintained patients’ lung function during short term use (≤ 1 month), and was the subject of positive feedback regarding functionality while reducing the risk of airway contamination associated with ineffective cleaning.RegistrationThe study was approved as a Clinical Investigation by the Irish Health Products Regulatory Authority (CRN-2209025-CI0085).

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).

Medical cannabis: What practitioners need to know.

The South African (SA) Constitutional Court recently decriminalised the private cultivation, possession and use of cannabis by adults. Cannabis contains varying amounts of the cannabinoids delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), depending on various cultivation factors. No commercial plant-derived cannabis products are currently registered by the SA Health Products Regulatory Authority (SAHPRA) for medical use. Such products are therefore unregulated, but are freely available in SA, and may be of inadequate quality and unverified composition, and not guaranteed to be safe or effective. SAHPRA has to date approved only one synthetic medical cannabis product, dronabinol. Evidence supporting benefit from medical cannabis exists for two drug-resistant childhood forms of epilepsy, Dravet syndrome and Lennox-Gastaut syndrome. Adjuvant therapy with medical cannabis can reduce seizure frequency for Lennox-Gastaut syndrome and Dravet syndrome by 18.8% and 22.8%, respectively, and may be beneficial for other rare forms of epilepsy. There is moderate evidence for chemotherapy-induced nausea and vomiting with the synthetic cannabinoids. Multiple sclerosis-associated spasticity showed a small clinical improvement in self-reported spasticity when a purified form of THC/CBD was added to existing therapy. Currently, low-level or no convincing evidence exists for the use of medical cannabis for chronic pain, sleep and weight disorders, and neuropsychiatric disorders. Cannabis is associated with a greater risk of adverse effects than active and placebo controls, and may be involved in clinically significant drug-drug interactions. The evolving regulatory and legal landscape on the use of medical cannabis will guide prescription and recreational use in the coming years.

Effectiveness and cost of integrating a pragmatic pathway for prescribing liraglutide 3.0 mg in obesity services (STRIVE study): study protocol of an open-label, real-world, randomised, controlled trial

IntroductionIn the UK and Ireland, severe and complex obesity is managed in specialist weight management services (SWMS), which provide multicomponent lifestyle interventions to support weight loss, and use of medication...

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.

Registration of amiloride in South Africa: Cutting the Gordian knot.

Amiloride is an antagonist of the renal tubular epithelial sodium channel (ENaC). As such, it is a diuretic that is both potassium and magnesium sparing. It is used for the treatment of potassium depletion and hypertension, and is the specific therapy for hypertension due to overactivity of the ENaC (Liddle syndrome and several additional genetic causes of the Liddle phenotype - low renin and low aldosterone). It is listed as a World Health Organization essential drug, but has never been registered in South Africa (SA) and can therefore only be prescribed under a Section 21 application to the SA Health Products Regulatory Authority (SAHPRA) on a case-by-case basis. In SA, >50% of patients treated for hypertension are not controlled. In the USA, the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study reported that African Americans are more likely to be diagnosed with hypertension, more likely to be treated, more likely to be treated intensively, and less likely to achieve blood pressure (BP) control. Although the reasons are complex, studies show that 10 - 20% of blacks may carry the Liddle phenotype. Observational data and a controlled clinical trial done in three African countries have shown that these patients respond to amiloride and not to conventional guideline-based antihypertensive treatment. The former is likely to result in a significant reduction in cardiovascular, stroke and kidney morbidity and mortality, because of improved BP control. Amiloride is very unlikely to ever be registered in SA, as it was first developed >50 years ago, and SAHPRA regulations prevent widespread prescription of this essential drug. This is a classic Gordian knot that requires a novel approach from authorities to sever the knot and improve the health of many South Africans.