WHO implementation workshop on guidelines on procedures and data requirements for changes to approved biotherapeutic products, Seoul, Republic of Korea, 25-26 June 2019.

The first global workshop on implementation of the WHO guidelines on procedures and data requirements for changes to approved biotherapeutic products adopted by the WHO Expert Committee in 2018 was held in June 2019. The workshop participants recognized that the principles based on sound science and the potential for risk, as described in the WHO Guidelines on post-approval changes, which constitute the global standard for product life-cycle management are providing clarity and helping national regulatory authorities in establishing guidance while improving time-lines for an efficient regulation of products. Consequently, the regulatory situation for post-approval changes and guideline implementation is changing but there is a disparity between different countries. While the guidelines are gradually being implemented in some countries and also being considered in other countries, the need for regional workshops and further training on post-approval changes was a common theme reiterated by many participants. Given the complexities relating to post-approval changes in different regions/countries, there was a clear understanding among all participants that an efficient approach for product life-cycle management at a national level is needed to ensure faster availability of high standard, safe and efficacious medicines to patients as per the World Health Assembly Resolution 67.21.

WHO informal consultation on development of guidelines on procedures and data requirements for changes to approved biotherapeutic products, Seoul, Republic of Korea, 27-28 April 2017.

In April 2017, WHO convened an informal consultation to develop WHO guidelines on procedures and data requirements for changes to approved biotherapeutic products. The objective of the meeting was to review the draft of WHO guidelines and the comments received from the public consultation. The guidelines were recognized by the participants as a tool for regulatory convergence and harmonization. Regulation of changes to approved biotherapeutic products is a key in ensuring that products of consistent quality, safety and efficacy are distributed after they receive authorization or licensure. Participants agreed that the guidelines would contribute to assuring the continued quality, safety and efficacy throughout the life-cycle of biotherapeutics as well as continuity in supply and access. In the meeting, participants further requested WHO should assist national regulatory authorities in improving technical expertise in the evaluation of biotherapeutics and their post-approval changes by organizing implementation workshops and developing case studies and e-training modules on various technical topics. At its meeting in October 2017, the WHO Expert Committee on Biological Standardization formally adopted the WHO guidelines on procedures and data requirements for changes to approved biotherapeutic products.

WHO working group on the quality, safety and efficacy of japanese encephalitis vaccines (live attenuated) for human use, Bangkok, Thailand, 21-23 February 2012.

Japanese encephalitis (JE) is one of the most important viral encephalitides in Asia. Two live-attenuated vaccines have been developed and licensed for use in countries in the region. Given the advancement of immunization of humans with increasing use of live-attenuated vaccines to prevent JE, there is increased interest to define quality standards for their manufacture, testing, nonclinical studies, and clinical studies to assess their efficacy and safety in humans. To this end, WHO convened a meeting with a group of international experts in February 2012 to develop guidelines for evaluating the quality, safety and efficacy of live-attenuated JE virus vaccines for prevention of human disease. This report summarizes collective views of the participants on scientific and technical issues that need to be considered in the guidelines.

Good recovery of immunization stress-related responses presenting as a cluster of stroke-like events following CoronaVac and ChAdOx1 vaccinations.

BACKGROUND: Immunization stress-related responses presenting as stroke-like symptoms could develop following COVID-19 vaccination. Therefore, this study aimed to describe the clinical characteristics of immunization stress-related responses causing stroke-like events following COVID-19 vaccination in Thailand. METHODS: We conducted a retrospective study of the secondary data of reported adverse events after COVID-19 immunization that presented with neurologic manifestations. Between March 1 and July 31, 2021, we collected and analyzed the medical records of 221 patients diagnosed with stroke-like symptoms following immunization. Two majority types of vaccines were used at the beginning of the vaccination campaign, including CoronaVac (Sinovac) or ChAdOx1 (AstraZeneca). Demographic and medical data included sex, age, vaccine type, sequence dose, time to event, laboratory data, and recovery status as defined by the modified Rankin score. The affected side was evaluated for associations with the injection site. RESULTS: Overall, 221 patients were diagnosed with immunization stress-related responses (stroke-like symptoms) following CoronaVac (Sinovac) or ChAdOx1 (AstraZeneca) vaccinations. Most patients (83.7%) were women. The median (interquartile range) age of onset was 34 (28-42) years in patients receiving CoronaVac and 46 (33.5-60) years in those receiving ChAdOx1. The median interval between vaccination and symptom onset for each vaccine type was 60 (16-960) min and 30 (8.8-750) min, respectively. Sensory symptoms were the most common symptomology. Most patients (68.9%) developed symptoms on the left side of the body; 99.5% of the patients receiving CoronaVac and 100% of those receiving ChAdOx1 had a good outcome (modified Rankin scores ≤2, indicating slight or no disability). CONCLUSIONS: Immunization stress-related responses presenting as stroke-like symptoms can develop after COVID-19 vaccination. Symptoms more likely to occur on the injection side are transient (i.e., without permanent pathological deficits). Public education and preparedness are important for administering successful COVID-19 vaccination programs.

An annual vaccine: seasonal influenza.

The accelerated development process for annual vaccines such as seasonal influenza presents unique challenges for the evaluation of vaccine stability. Real-time real-condition studies provide limited information at the time of registration, while regulators seek evidence that the current vaccine will perform satisfactorily in the field. Participants in the IABS Workshop on Stability Evaluation of Vaccines, a Life Cycle Approach, were offered a case study from the development of the 2007 influenza vaccine. The case study was introduced with preliminary data from the long-term study, as well as results from the completed year long study. The manufacturer also offered a proposed protocol for stability evaluation of vaccines developed in subsequent seasons. Participants were asked to answer a series of questions posed by the regulator, and critique the proposed stability protocol according to the principles described during the workshop.

A vaccine measured with a highly variable assay: rabies.

Manufacturers and regulators are challenged when evaluating stability of vaccines when potency is measured using a highly variable assay. Participants in the IABS Workshop on Stability Evaluation of Vaccines, a Life Cycle Approach, were offered a case study from a series of stability studies of a rabies vaccine, using the NIH potency assay. The case study was introduced with a scenario in which a new manufacturer was to formulate, lyophilize and fill the vaccine from bulk supplied by another manufacturer. The regulatory authority requested that data from the new manufacturer be supplied, to supplement that of the original producer. Participants were asked to answer a series of questions posed by the regulator, and critique the study design and data analysis according to principles described during the workshop.

A global regulatory science agenda for vaccines.

The Decade of Vaccines Collaboration and development of the Global Vaccine Action Plan provides a catalyst and unique opportunity for regulators worldwide to develop and propose a global regulatory science agenda for vaccines. Regulatory oversight is critical to allow access to vaccines that are safe, effective, and of assured quality. Methods used by regulators need to constantly evolve so that scientific and technological advances are applied to address challenges such as new products and technologies, and also to provide an increased understanding of benefits and risks of existing products. Regulatory science builds on high-quality basic research, and encompasses at least two broad categories. First, there is laboratory-based regulatory science. Illustrative examples include development of correlates of immunity; or correlates of safety; or of improved product characterization and potency assays. Included in such science would be tools to standardize assays used for regulatory purposes. Second, there is science to develop regulatory processes. Illustrative examples include adaptive clinical trial designs; or tools to analyze the benefit-risk decision-making process of regulators; or novel pharmacovigilance methodologies. Included in such science would be initiatives to standardize regulatory processes (e.g., definitions of terms for adverse events [AEs] following immunization). The aim of a global regulatory science agenda is to transform current national efforts, mainly by well-resourced regulatory agencies, into a coordinated action plan to support global immunization goals. This article provides examples of how regulatory science has, in the past, contributed to improved access to vaccines, and identifies gaps that could be addressed through a global regulatory science agenda. The article also identifies challenges to implementing a regulatory science agenda and proposes strategies and actions to fill these gaps. A global regulatory science agenda will enable regulators, academics, and other stakeholders to converge around transformative actions for innovation in the regulatory process to support global immunization goals.