World Health Organization Prequalification Research Articles

Measles–Rubella Microarray Patches Phase III Clinical Trial Framework: Proposal and Considerations

Background: The Measles–Rubella Microarray Patch (MR-MAP) is an important technology that is expected to reduce coverage and equity gaps for measles-containing vaccines (MCVs), reach zero-dose children, and contribute to elimination of measles and rubella. MR-MAPs are anticipated to be easier to deploy programmatically and could be delivered by lesser-trained health workers, thereby increasing immunization coverage. The most advanced MR-MAP has reached clinical proof-of-concept through a Phase I/II trial in the target population of infants and young children. The World Health Organization (WHO) and partners have developed the Phase III clinical trial framework for MR-MAPs presented in this article. Objectives and Methods: The purpose of such framework is to inform the considerations, design and approach for the pivotal clinical trial design, while considering the anticipated data requirements to inform regulatory approval, WHO prequalification, and policy decision. Results: The proposed Phase III trial would compare the immunogenicity and safety of an MR-MAP with MR vaccine delivered subcutaneously in 9- to 10-month-old infants. An analysis of non-inferiority (NI) of immunogenicity would occur six weeks after the first dose. Should regulatory agencies or policy makers require, a proportion of infants could receive a second dose of either the same or alternate MR vaccine presentation six months after the first dose, with those children returning six weeks after the second dose for a descriptive assessment of immunogenicity, and then followed up six months after the second dose for evaluation of safety and immunogenicity. It is anticipated that this proposed pivotal Phase III trial framework would generate the required clinical data for regulatory licensure and WHO prequalification (PQ) of MR-MAPs. However, the trial design would need to be reviewed and confirmed by a national regulatory authority (NRA) that will assess the product for regulatory licensure and the WHO PQ team. Additional research will likely be required to generate data on concomitant vaccine delivery, the safety and immunogenicity of MR-MAPs in other age groups such as children 1–5 years and infants younger than 9 months of age, and the impact of MR-MAPs on coverage and equity. Such studies could be conducted during or after clinical MR-MAP development.

Barriers to WHO prequalification of similar biotherapeutic insulin.

To identify the barriers preventing manufacturers of similar biotherapeutic human insulin from submitting their products to the World Health Organization (WHO) for prequalification. We used a self-administered questionnaire to collect data from companies producing similar biotherapeutic human insulin. We included questions about the insulin products manufactured, knowledge of WHO prequalification requirements, export of the products and compliance with good manufacturing practices. Companies had the possibility to provide additional relevant information. We sent the questionnaire to 20 manufacturers in total. We evaluated responses and organized the data into themes. We had a response rate of 55% (11/20 companies). Five broad themes emerged: (i)manufacturers and products; (ii)expressions of interest awareness and participation; (iii)need for technical assistance and training; (iv)market and supply chain challenges; and (v)approval for good manufacturing practices. The most important reasons for manufacturers' lack of response to WHO's expression-of-interest invitation were absence of a mechanism to guarantee return on investment, and perceived complexity of prequalification requirements for insulin-similar biotherapeutic products. To encourage greater participation in the WHO prequalification programme, international procurement agencies associated with the programme should consider establishing a platform to enter into advance purchasing agreements with manufacturers. In addition, WHO's Local Production and Assistance Unit should provide companies with ongoing technical assistance on the development of their human insulin products and improvement of their production facilities to comply with the WHO requirements for good manufacturing practices.

Knowledge-based: facilitating access to medicines in Latin America

The World Health Organization (WHO), with the scientific support of the International Pharmaceutical Federation (FIP), guides the development of multisource pharmaceutical products for market authorization using in vivo bioequivalence studies or, where applicable, in vitro biowaiver strategies based on the Biopharmaceutical Classification System (BCS). A review of the regulatory framework guiding generic medicines approval in Latin American countries revealed that less than 50% of regional health authorities offer a generic medicines development pathway utilizing a BCS-based biowaiver strategy. Aligned with the ONE FIP Strategy to facilitate access to medicines, a regional case study was carried out to implement and harmonize BCS-based biowaiver knowledge in Latin American countries. A steering committee involving regional representatives from health authorities, the pharmaceutical industry, and universities were established to coordinate to develop activities. A series of digital engagement events were held in Spanish and English with representatives from Latin America to share knowledge on BCS-based regulatory strategy, promote collaborations, and explore the alignment of biowaiver approval and regulatory pathways among Latin American countries. Feedback from diverse Latin American stakeholders demonstrated inconsistent implementation of bioequivalence testing within the region. However, there is support for a synergistic approach among countries to reduce duplication and increase efficiency in market authorization for generic medicines. This includes alignment with the WHO Prequalification of Medicines program as well as the development of a computational database for the classification of active pharmaceutical ingredients to demonstrate therapeutic interchangeability of immediate-release oral dosage forms according to the BCS. FIP-facilitated digital learning opportunities raised awareness of the BCS-based biowaiver regulatory strategy among Latin American stakeholders. It resulted in a plan to continually strengthen collaborative efforts in the region to harmonize regulations relevant to drug development generics medicines to introduce cost-effective medicines products that benefit public health.

Novel Oral Polio Vaccine Type 2 Use for Polio Outbreak Response: A Global Effort for a Global Health Emergency.

A sharp rise in circulating vaccine-derived poliovirus type 2 (cVDPV2) outbreaks in the years following the cessation of routine use of poliovirus type 2-containing oral polio vaccine and the trend of seeding new emergences with suboptimal vaccination response during the same time-period led to the accelerated development of the novel oral polio vaccine type 2 (nOPV2), a vaccine with enhanced genetic stability and lower likelihood of reversion to neuroparalytic variants compared to its Sabin counterpart. In November 2020, nOPV2 became the first vaccine to be granted an Emergency Use Listing (EUL) by the World Health Organization (WHO) Prequalification Team (PQT), allowing close to a billion doses to be used by countries within three years after its first rollout and leading to full licensure and WHO prequalification (PQ) in December 2023. The nOPV2 development process exemplifies how scientific advances and innovative tools can be applied to combat global health emergencies in an urgent and adaptive way, building on a collaborative effort among scientific, regulatory and implementation partners and policymakers across the globe.

Exploring the feasibility of introducing triple artemisinin-based combination therapy in the malaria treatment policy in Vietnam

BackgroundThis study investigates the processes regarding changing malaria treatment policies in Vietnam. Moreover, it explores the feasibility of introducing triple artemisinin-based combination therapy (TACT) in Vietnam to support the national malaria control and elimination plan.MethodsData were collected via 12 in-depth interviews with key stakeholders, combined with a review of policy documents.ResultsTACT is considered as a useful backup strategy in case future treatment failures with current artemisinin-based combination therapy (ACT) would occur. Moreover, TACT is also considered as a promising strategy to prevent the re-establishment of malaria. However, regulatory procedures and implementation timelines for TACT were expected to be lengthy. Therefore, strategies to engage national decision-makers, regulators, and suppliers should be initiated soon, stipulating the benefits of TACT deployment. In Vietnam, a procedure to apply for an import permit without registration that has previously been applied to the introduction of artesunate-pyronaridine was proposed to accelerate the introduction of TACT. Global-level support through the World Health Organization recommendations and prequalification were considered critical for supporting the introduction of TACT in Vietnam.ConclusionsAppropriate approach strategies and early stakeholder engagement will be needed to accelerate the introduction of TACT in Vietnam.

Global regulatory reforms to promote equitable vaccine access in the next pandemic.

There is broad consensus that the global response to the Covid-19 pandemic was inadequate, leading to unacceptable levels of avoidable morbidity and mortality. Three strategic missteps led to the lack of equitable vaccine access: The heavy reliance on commercial vaccine manufacturers in high-income countries (HICs) versus low- and middle-income countries (LMICs); the emergence of vaccine nationalism restricting and delaying the supply of vaccines to LMICs; and an inadequate support or recognition for LMIC national regulatory authorities. To avoid these inequities in a future pandemic, we focus on three successful vaccine development and technology transfer case studies-the Hepatitis B vaccine produced in South Korea in the 1980s; the Meningitis A vaccine for Africa led by Program for Appropriate Technologies in Health (PATH) and the World Health Organization (WHO) in the 2000s; and a recombinant SARS CoV-2 protein-based vaccine technology from the Texas Children's Hospital transferred to India and to Indonesia. In addition to expanding support for academic or non-profit product development partnerships, our analysis finds that an essential step is the strengthening of selected LMIC regulatory systems to become Stringent Regulatory Authorities (SRAs), together with a re-prioritization of the WHO Prequalification (PQ) system to ensure early vaccine availability in LMICs especially during pandemics. Advancing LMIC National Regulatory Authorities (NRAs) to Stringent Regulatory Authorities (SRAs) status will require substantial resources, but the benefits for future pandemic control and for health in LMIC would be immense. We call on the WHO, United Nation (UN) agencies and SRAs, to collaborate and implement a comprehensive roadmap to support LMIC regulators to achieve stringent status by 2030.

Taking on Typhoid: Eliminating Typhoid Fever as a Global Health Problem.

Typhoid fever is a significant global health problem that impacts people living in areas without access to clean water and sanitation. However, collaborative international partnerships and new research have improved both knowledge of the burden in countries with endemic disease and the tools for improved surveillance, including environmental surveillance. Two typhoid conjugate vaccines (TCVs) have achieved World Health Organization prequalification, with several more in the development pipeline. Despite hurdles posed by the coronavirus disease 2019 pandemic, multiple TCV efficacy trials have been conducted in high-burden countries, and data indicate that TCVs provide a high degree of protection from typhoid fever, are safe to use in young children, provide lasting protection, and have the potential to combat typhoid antimicrobial resistance. Now is the time to double down on typhoid control and elimination by sustaining progress made through water, sanitation, and hygiene improvements and accelerating TCV introduction in high-burden locations.

Diagnostic Accuracy of Human Immunodeficiency Virus In Vitro Assays Evaluated by the World Health Organization Prequalification Evaluation Laboratories: Systematic Review and Meta-Analysis.

To maintain the performance quality, human immunodeficiency virus (HIV) in vitro diagnostic (IVD) kits are required to be evaluated by unbiased health regulatory organizations following predefined guidelines. The World Health Organization (WHO) prequalification is one such program for the evaluation of IVD assays. In the present systematic review and meta-analysis, we analyzed and compared the 17 WHO prequalified public reports of HIV IVDs to yield summarized information for performance parameters. Pooled sensitivity, pooled specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio were used as overall performance evaluation parameters. High (≥98%) and comparable levels of sensitivity and specificity were observed for most of the assays. In addition, the overall diagnostic efficiency was observed to attain high precision, as evident by the value of the area under the curve (AUC) for the hierarchical summary receiver operating characteristic curve (AUC ≥ 0.98).

Efficacy and Effectiveness of the Meningococcal Conjugate Group A Vaccine MenAfriVac® in Preventing Recurrent Meningitis Epidemics in Sub-Saharan Africa.

For more than a century, epidemic meningococcal disease mainly caused by serogroup A Neisseria meningitidis has been an important public health problem in sub-Saharan Africa. To address this problem, an affordable meningococcal serogroup A conjugate vaccine, MenAfriVac®, was developed specifically for populations in the African meningitis belt countries. MenAfriVac® was licensed based on safety and immunogenicity data for a population aged 1–29 years. In particular, the surrogate markers of clinical efficacy were considered to be the higher immunogenicity and the ability to prime immunological memory in infants and young children compared to a polysaccharide vaccine. Because of the magnitude of serogroup A meningitis epidemics and the high morbidity and mortality burden, the World Health Organization (WHO) recommended the MenAfriVac® deployment strategy, starting with mass vaccination campaigns for 1–29-year-olds to rapidly interrupt serogroup A person-to-person transmission and establish herd protection, followed by routine immunization of infants and toddlers to sustain protection and prevent epidemics. After licensure and WHO prequalification of MenAfriVac®, campaigns began in December 2010 in Burkina Faso, Mali, and Niger. By the middle of 2011, it was clear that the vaccine was highly effective in preventing serogroup A carriage and disease. Post introduction meningitis surveillance revealed that serogroup A meningococcal disease had disappeared from all age groups, suggesting that robust herd immunity had been achieved.

Efavirenz listed in the World Health Organization Prequalification Program: A successful case study of a public private collaboration for technology transfer in pharmaceutical production and quality control in Thailand

Efavirenz listed in the World Health Organization Prequalification Program: A successful case study of a public private collaboration for technology transfer in pharmaceutical production and quality control in Thailand

Science, Innovation, and Society in the Age of Pandemics: Reflections From the Inaugural Sir Alasdair Breckenridge Lecture.

Science, Innovation, and Society in the Age of Pandemics: Reflections From the Inaugural Sir Alasdair Breckenridge Lecture.

Hepatitis E vaccines: A mini review

The hepatitis E virus (HEV) is an important public health concern and a significant cause of enterically-transmitted viral hepatitis infections. HEV infection remains a serious threat to life, especially in immunocompromised individuals and pregnant women. Globally, vaccines have had a massive impact on public health and saved millions of lives. Vaccination can reduce the healthcare expenditure, decrease the mortality rate, and increase life expectancy. The availability of commercially effective vaccines is the most effective means for the prevention of HEV. However, the development of classic inactive or attenuated HEV vaccines is not feasible due to the lack of an efficient cell culture system for HEV. In recent years, recombinant HEV vaccine approaches have been explored. Many vaccine candidates have showed potential efficacy against HEV infection. Currently, the only licensed vaccine is Hecolin®, a recombinant vaccine developed by Xiamen Innovax Biotech Co., Ltd. It is available in China. However, there are many hindrances when it comes to the acrossthe- board application of Hecolin® and other vaccines worldwide. Large-scale efforts are needed to further evaluate the efficacy and safety of Hecolin® in at-risk populations and to pass the World Health Organization prequalification for licensing outside of China.

Performance assessment of four HIV self-test devices in South Africa: A cross-sectional study

HIV self-testing (HIVST) has been introduced to supplement existing HIV testing methods to increase the number of people knowing their HIV status. Various HIVST kits have been developed; however, in many countries, their entry into the market is contingent on either being listed as World Health Organization (WHO) prequalified diagnostics/products or being approved by that country’s health device regulator or both. In this cross-sectional study, we evaluated the usability, sensitivity and specificity of HIVSTs, as directed by the WHO prequalification literature. A boxed, sealed HIVST kit was provided to enrolled lay users with no further instruction, who then performed the test under observation. For each HIVST, a product-specific semi-structured checklist was used to calculate a usability index, while the sensitivity and specificity of each HIVST were calculated by comparing the HIVST results to the ‘gold standard’ – fourth-generation ELISA laboratory blood test. The average usability index was 97.1% (95.9–97.8%), while the average sensitivity and specificity were 98.2% (96.8–99.3%) and 99.8% (99.4–100.0%), respectively. We also diagnosed 507 (15.1%) HIV-positive participants from the general population. The average usability index, sensitivity and specificity were all comparatively high, and these results corroborate previous usability and performance studies from other regions. These results suggest HIVSTs are appropriate for the South African market and can assist manufacturers with readying their devices for final WHO prequalification evaluation.
 Significance:
 
 This study has followed the WHO Technical Specification Series for the prequalification of HIV self-test devices, so the usability, sensitivity and specificity results may be used to inform the WHO prequalification process.
 The average usability index (97.1%), sensitivity (98.2%) and specificity (99.8%) were all very high, and these results support previous usability and performance studies from other regions, which suggest HIV self-tests are appropriate for WHO prequalification, and subsequently, the South African market.
 This study also diagnosed 507 (15.1%) HIV-positive participants from the general population – slightly higher than the national prevalence of 13.1%.

Sensitivity and specificity of rapid hepatitis C antibody assays in freshly collected whole blood, plasma and serum samples: A multicentre prospective study.

This study evaluated performance of two hepatitis C virus (HCV) rapid diagnostic tests (RDTs) performed by intended users in resource-limited settings. Testing was conducted at three facilities in two countries (Georgia, Cambodia) using matched fingerstick whole blood, plasma and serum samples. Investigational RDTs were compared with a composite reference standard (CRS) comprised of three laboratory tests, and a reference RDT. In matched samples from 489 HCV positive and 967 HCV negative participants, specificity with both investigational RDTs was high using either reference method (≥98.4% in all sample types). Sensitivity was lower in whole blood versus plasma and serum for both RDTs compared with the CRS (86.5-91.4% vs 97.5-98.0% and 97.3-97.1%) and reference RDT (93.6-97.8% vs 100% and 99.4%). Sensitivity improved when considering only samples with detectable HCV viral load. Sensitivity was highest in serum and plasma versus whole blood. The World Health Organization prequalification criterion (≥98%) was narrowly missed by both RDTs in serum, and one in plasma, possibly due to the intended user factor. Performance in whole blood was considered adequate, given potential roles of HCV infection history, improved sensitivity with detectable viral load and performance similarities to the reference RDT.

Alignment in post-approval changes (PAC) guidelines in emerging countries may increase timely access to vaccines: An illustrative assessment by manufacturers

A comparison of the regulations and guidelines from 33 countries, across different regions, on the requirements and procedures for the management of chemical, manufacturing and control (CMC) changes for vaccines, also known as post- approval changes (PACs), reveals significant variability and lack of predictability of timelines for regulatory review and approval. These shortcomings imply that multiple data packages have to be prepared for submission to different authorities, generating a complex regulatory environment. Moreover, the timelines for approval by individual national regulatory authorities are variable, which results in manufacturers keeping various stocks of vaccines produced in accordance with the various approved specifications and procedures, in the different countries. This can seriously affect timely availability of vaccine in those countries. The World Health Organization (WHO) guidelines on procedures and data requirements for changes to approved vaccines provide a consensual framework for alignment, but are still underused. Reliance on both the review and approval by the regulatory authority in the country of manufacturing, or on the review performed by other national regulatory authorities, recognized by WHO as stringent, or on WHO prequalification dossier, offer alternative ways forward. These and other options to improve the management of post-approval changes during the product lifecycle of vaccines are discussed in this report, and aimed at improving guidelines alignment and regulatory convergence to advance immunization equity and coverage.

Assessing the Feasibility of Typhoid Elimination.

In 1993, the International Task Force on Disease Eradication classified the political will for typhoid eradication as “none.” Here we revisit the Task Force’s assessment in light of developments in typhoid vaccines and increasing antimicrobial resistance in Salmonella Typhi that have served to increase interest in typhoid elimination. Considering the requisite biological and technical factors for elimination, effective interventions exist for typhoid, and humans are the organism’s only known reservoir. Improvements in water supply, sanitation, hygiene, and food safety are critical for robust long-term typhoid control, and the recent Strategic Advisory Group of Experts on Immunization recommendation and World Health Organization prequalification should make typhoid conjugate vaccine more accessible and affordable in low-income countries, which will allow the vaccine to offer a critical bridge to quickly reduce burden. While these developments are encouraging, all current typhoid diagnostics are inadequate, having either poor performance characteristics, limited scalability, or both. No clear solution exists, and this should be viewed as a critical challenge to any elimination effort. Moreover, asymptomatic carriers and limited data and surveillance remain major challenges, and countries considering elimination campaigns will need to develop strategies to identify high-risk populations and to monitor progress over time. Finally, policymakers must be realistic in planning, learn from the planning failures of previous elimination and eradication efforts, and expect unforeseeable shocks and setbacks. In the end, if we assume neither unanticipated breakthroughs in typhoid control nor any chaotic shocks, history suggests that we should expect typhoid elimination to take decades.

The impact of maternal RSV vaccine to protect infants in Gavi-supported countries: Estimates from two models

BackgroundInterventions to protect young infants against respiratory syncytial virus (RSV) are in advanced phases of development and are expected to be available in the foreseeable future. Gavi, the Vaccine Alliance, included maternal vaccines and infant monoclonal antibodies for RSV as part of the 2018 vaccine investment strategy (VIS) and decided to support these products subject to licensure, World Health Organization prequalification, Strategic Advisory Group of Experts recommendation, and meeting the financial assumptions used as the basis of the investment case. Impact estimates reported in this manuscript were used to inform the Gavi VIS. MethodsWe compared two independent vaccine impact models to evaluate a potential maternal RSV vaccine’s impact on infant health in 73 Gavi-supported countries. Key inputs were harmonized across both models. We analyzed various scenarios to evaluate the effect of uncertain model parameters such as vaccine efficacy, duration of infant protection, and infant disease burden. Estimates of averted cases, severe cases, hospitalizations, deaths, and disability-adjusted life years (DALYs) were calculated over the 2023–2035 horizon. FindingsA maternal RSV vaccine with 60% efficacy offering 5 months of infant protection implemented across 73 low- and middle-income countries could avert 10.1–12.5 million cases, 2.8–4.0 million hospitalizations, 123.7–177.7 thousand deaths, and 8.5–11.9 million DALYs among infants under 6 months of age for the duration of analysis (2023–2035). Maternal RSV vaccination was projected to avert up to 42% of estimated RSV deaths among infants under 6 months in year 2035. Alternative scenario analyses with higher disease burden assumptions showed that a maternal vaccine could avert as many as 325–355 thousand deaths among infants under 6 months. InterpretationRSV maternal immunization is projected to substantially reduce mortality and morbidity among young infants if introduced across Gavi-supported countries. FundingThis work was supported by Bill & Melinda Gates Foundation, Seattle, WA, and Respiratory Syncytial Virus Consortium in Europe. The findings and conclusions contained within are those of the authors and do not necessarily reflect positions or policies of the Bill & Melinda Gates Foundation or of the Respiratory Syncytial Virus Consortium. LW is supported by Research Foundation–Flanders (1234620 N).

Sudden Sensorineural Hearing Loss after Lapaoscopic Sleeve Gastrectomy Under General Anaesthesia: A Case Report

In March 2001, World Health Organization (WHO) Prequalification of Medicines Program (PQP) comes in action...

A survey of nongovernmental organizations on their use of WHO's prequalification programme.

ObjectiveTo obtain the perspectives of some small- and medium-sized organizations on the World Health Organization (WHO) prequalification programme for medicines and to ascertain organizations’ unmet needs.MethodsWe conducted an exploratory, qualitative study in 2018 among 17 representatives of 15 small- and medium-sized Belgian and non-Belgian organizations who purchase medicines for humanitarian, development or public programmes in low- and middle-income countries. We used semi-structured interviews to obtain respondents’ views and experiences of using WHO prequalification guidance when procuring medicines. We identified emerging themes and formulated recommendations about the activities of the WHO Prequalification Team.FindingsMost respondents suggested expanding prequalification to essential antibiotics, particularly paediatric formulations; and insulin, antihypertensives and cancer treatments. Respondents were concerned about irregular availability of WHO-prequalified medicines in the marketplace and sometimes high prices of prequalified products. Small organizations, in particular, had difficulties negotiating low-volume purchases. Organizations working in primary health care and hospitals seldom referred to the prequalified lists.ConclusionWe recommend that the WHO-prequalified products be expanded to include essential antibiotics and medicines for noncommunicable diseases. The WHO Prequalification Team could require prequalified manufacturers to make publicly available the details of their authorized distributors and facilitate a process of harmonization of quality assurance policies across all donors. Prequalification of distributors and procurement agencies could help create more transparent and stringent mechanisms. We urge WHO Member States and funders to sustain support for the WHO Prequalification Team, which remains important for the fulfilment of universal health coverage.

Immunogenicity and safety of lyophilized and liquid dengue tetravalent vaccine candidate formulations in healthy adults: a randomized, phase 2 clinical trial

ABSTRACT Takeda has developed a live-attenuated dengue tetravalent vaccine candidate (TAK-003) which has been shown to be immunogenic with acceptable reactogenicity in phase 1 trials. In agreement with World Health Organization prequalification requirements for dengue vaccines, Takeda has manufactured a lyophilized formulation of TAK-003 that allows stable storage at +2°C to +8°C. This randomized, double-blind, phase 2 study (NCT02193087) was performed in 1002 healthy dengue-naïve adults, 18–49 years of age, across seven centers in the USA to compare the safety and immunogenicity of one or two doses of a lyophilized TAK-003 formulation with the liquid TAK-003 formulation used in previous phase 1 studies. The primary objective was to show immunologic equivalence in terms of geometric mean titers (GMT) of neutralizing antibodies to the four dengue serotypes one month after one dose of the lyophilized and liquid formulations. Secondary assessments were of safety and seropositivity rates, including after a second dose. The primary endpoint was not met, because immunologic equivalence after one dose was only shown for the DENV-2 serotype. Nonetheless, GMTs and seropositivity rates to all four serotypes were achieved with all formulations after two doses and are in line with what was observed in previous studies. Additionally, in view of the acceptable reactogenicity, with no vaccine-related serious adverse events reported, these data support continuing further clinical development of the lyophilized TAK-003 formulation.